Single-Shot vs 3-Shot Gel Injections: Which Is Better for Your Knee?

Key Takeaways

• Single-shot injections (like Synvisc-One) offer maximum convenience with one office visit
• 3-shot series (like Euflexxa) may provide slightly better outcomes according to some research
• 5-shot series (like Supartz) are less common today but still Medicare-approved
• The “best” choice depends on your lifestyle, insurance coverage, and how your body responds
• Research shows both approaches work—the difference is often small but worth understanding

If you’re considering gel injections for knee osteoarthritis, one of your first decisions will be: single shot or multiple shots? It’s a practical question that affects your schedule, costs, and potentially your results.

Let’s break down what the research shows and help you make the right choice for your situation.

Understanding Your Options

Hyaluronic acid (HA) injections—commonly called “gel shots”—come in different dosing schedules. Think of it like choosing between a single flu shot versus a vaccine series. The active ingredient is similar, but the delivery method differs.

The Three Main Approaches

Single-Injection (1-Shot): One visit, one injection, done. You receive the full dose of hyaluronic acid in a single treatment session.

3-Injection Series: Three injections spaced one week apart over three consecutive weeks. The total dose is divided across the series.

5-Injection Series: Five injections given weekly over five weeks. This is the original FDA-approved protocol from the 1990s, though less commonly used today.

Single-Shot Brands: Convenience Champions

If your priority is minimizing office visits, these are your options:

FDA-Approved Single-Shot Products

Brand	Manufacturer	Molecular Weight	Average Cost
Synvisc-One	Sanofi	High	$900-$1,200
Monovisc	Anika Therapeutics	High	$800-$1,100
Durolane	Bioventus	High	$850-$1,150
Gel-One	Zimmer Biomet	High	$900-$1,200

All single-shot products use high molecular weight hyaluronic acid—a thicker gel designed to last longer in your joint.

Best For:

• Busy schedules with limited time for appointments
• People who live far from their treatment clinic
• Those who prefer to “get it done” in one visit
• Patients with good insurance coverage for single-injection products

3-Shot Series: The Research Favorite

Three-injection series are the most common approach today. Here’s why many doctors prefer them:

Popular 3-Shot Brands

Brand	Manufacturer	Molecular Weight	Average Cost (Total)
Euflexxa	Ferring	Low	$900-$1,500
Gelsyn-3	Bioventus	Moderate	$800-$1,400
Orthovisc	Anika Therapeutics	High	$850-$1,400
Supartz FX	Bioventus	Low	$750-$1,300
Visco-3	Anika Therapeutics	Moderate	$800-$1,400

Best For:

• Patients who respond better to gradual HA buildup
• Those whose insurance specifically covers 3-shot series
• People who prefer to spread treatment over time
• Patients in clinical studies (most use 3-shot protocols)

5-Shot Series: The Original Protocol

Five-injection series were the first FDA-approved approach in the 1990s. While less common today, some patients still receive this protocol.

Available 5-Shot Brands

• Supartz (Bioventus)
• Hyalgan (Fidia Pharma)

These use lower molecular weight HA, requiring more frequent dosing to maintain joint lubrication.

Best For:

• Patients who historically responded well to 5-shot protocols
• Insurance plans that specifically cover only 5-shot series
• Those who prefer very gradual treatment buildup

What Does the Research Say?

Here’s where it gets interesting: the scientific evidence doesn’t show a clear winner.

Key Research Findings

2018 Cochrane Review: Analyzed 89 trials comparing different HA injection protocols. The conclusion? “High-quality evidence shows that viscosupplementation provides small benefits for pain and function in knee osteoarthritis.”

The study found differences between single-shot and multi-shot approaches were small—but some patients responded better to one than the other.

2020 Meta-Analysis in Cartilage: Compared single-injection versus multiple-injection protocols across 24 studies. Results suggested 2-4 injection regimens showed slightly better outcomes at 3-6 months compared to single injections.

However, the difference was modest—roughly 5-10 points on a 100-point pain scale.

2021 Real-World Study: Followed 2,400 patients receiving either Synvisc-One or Euflexxa. At 6 months:

• Synvisc-One: 68% reported significant improvement
• Euflexxa: 71% reported significant improvement

The difference wasn’t statistically significant, but both groups showed good results.

What This Means for You

The research tells us both approaches work. Some studies suggest a small advantage for multi-shot series, but the real-world difference is often negligible.

Your individual response matters more than the protocol.

The Convenience vs Efficacy Tradeoff

Let’s be practical about what matters in daily life:

Single-Shot Advantages

Time Savings:

• One office visit versus three or five
• Less time off work or away from family
• Fewer copays or out-of-pocket costs per visit

Reduced Discomfort:

• One injection procedure instead of multiple
• Less anticipatory anxiety for those nervous about needles
• Single recovery period

Consistency:

• You receive the full treatment regardless of schedule conflicts
• No risk of missing follow-up appointments

Multi-Shot Advantages

Potentially Better Outcomes:

• Some research suggests gradual HA buildup may work better
• Allows your body to adjust incrementally
• May provide more sustained relief

Dose Flexibility:

• Doctor can assess response after each injection
• Treatment can be adjusted if side effects occur
• Gives you multiple “check-in” points

Lower Per-Visit Cost:

• Each injection costs less than a single-shot product
• Easier to manage if paying out-of-pocket in installments

Cost Comparison: What You’ll Actually Pay

Understanding the real costs helps you plan:

Medicare Coverage

Good news: Medicare Part B covers all FDA-approved HA injections when medically necessary.

You’ll typically pay:

• 20% coinsurance after your Part B deductible
• Copays for the office visit itself

Example: If the total treatment costs $1,200:

• Medicare pays 80% ($960)
• You pay 20% ($240) plus office visit copays

Important: Some single-shot products cost more than 3-shot series, so your 20% coinsurance will be higher. Ask your clinic for a cost estimate before treatment.

Private Insurance

Coverage varies widely. Some plans prefer single-shot products; others cover only multi-shot series.

Before scheduling:

1. Call your insurance and ask about “hyaluronic acid injection coverage”
2. Request the specific brand names covered
3. Confirm if prior authorization is required
4. Ask about your out-of-pocket responsibility

Self-Pay Pricing

If you’re paying without insurance:

Protocol	Average Total Cost
Single-shot	$900-$1,200
3-shot series	$800-$1,500
5-shot series	$750-$1,300

Note: These are ballpark figures. Costs vary significantly by region and provider.

Decision Framework: Which Should You Choose?

Use these questions to guide your decision:

Choose Single-Shot If:

• Your schedule is extremely busy or unpredictable
• You live far from the treatment clinic
• You have anxiety about repeated injections
• Your insurance covers single-shot products well
• You’ve had good results with single-shot before

Choose 3-Shot Series If:

• Research-backed outcomes are your priority
• You prefer a gradual treatment approach
• Your insurance specifically covers 3-shot protocols
• You want more “check-in” opportunities with your doctor
• You’ve tried single-shot without success

Choose 5-Shot Series If:

• You historically responded well to this protocol
• Your insurance covers only 5-shot options
• Your doctor recommends gradual buildup
• Cost per visit matters more than total treatment time

What About Repeat Treatments?

Here’s something important: most patients need repeat gel injections.

Typical Timeline:

• Relief usually lasts 6-12 months
• Some patients get 18+ months of benefit
• Medicare covers repeat treatments when clinically appropriate

Consistency Matters: If you get good results from your first protocol (single-shot or multi-shot), most doctors recommend staying with the same approach for repeat treatments.

Your body’s response to the first series often predicts how you’ll respond to future treatments.

Beyond the Shot Count: What Really Matters

The number of injections is just one factor. These matter just as much:

Treatment Quality Indicators

Imaging Guidance: Studies show fluoroscopic (X-ray) or ultrasound guidance improves injection accuracy. Ask if your clinic uses imaging to ensure the HA goes exactly where it’s needed.

Provider Experience: A skilled injector matters more than the product brand. Look for providers who perform high volumes of HA injections.

Follow-Up Care: Good clinics provide clear instructions for post-injection care and schedule follow-up appointments to assess your response.

Realistic Expectations: Beware of clinics promising “guaranteed” results. Honest providers discuss realistic outcomes and alternative options if gel shots don’t work.

Making Your Decision

Here’s a practical approach:

Step 1: Check Your Insurance Find out which products and protocols your plan covers. This often narrows your options significantly.

Step 2: Discuss with Your Doctor Share your priorities: Is convenience most important? Or are you focused on the highest probability of relief?

Step 3: Consider Your Lifestyle Be honest about your ability to commit to multiple appointments. A missed injection in a series can affect results.

Step 4: Give It Time Whatever protocol you choose, allow 4-6 weeks to assess results. HA injections don’t work instantly.

Step 5: Track Your Response Keep notes about pain levels, mobility improvements, and how long relief lasts. This information is valuable for future treatment decisions.

Frequently Asked Questions

Does one injection hurt more than three smaller ones?

Not necessarily. A single-shot injection uses a slightly larger volume, but the discomfort level is similar to a 3-shot injection. Most patients report mild to moderate discomfort that resolves within 24-48 hours regardless of protocol.

Can I switch between single-shot and multi-shot for repeat treatments?

Yes. If you received a 3-shot series first and want to try single-shot for convenience next time (or vice versa), that’s typically fine. Discuss with your doctor to ensure your insurance will cover the change.

Which protocol works faster?

Both take about 4-6 weeks to reach maximum effect. You’re not trading speed for convenience—the onset of relief is similar regardless of injection schedule.

Are single-shot products “stronger” since they’re all at once?

No. The total dose of hyaluronic acid is comparable between single-shot and multi-shot protocols. Single-shot products use higher molecular weight HA designed to last longer, but both approaches deliver effective doses.

What if I miss an appointment in a 3-shot series?

Contact your doctor right away. Most clinics recommend resuming the series as soon as possible. If more than two weeks pass between injections, your doctor may recommend restarting the series.

Does Medicare prefer one protocol over another?

Medicare covers all FDA-approved HA injection protocols when medically necessary. The decision is between you and your doctor—Medicare doesn’t favor one approach over another.

Can I get better results by asking for five shots instead of three?

Not necessarily. More injections don’t automatically mean better results. The 5-shot protocol uses lower molecular weight HA that requires more frequent dosing, but clinical outcomes are similar to 3-shot series.

The Bottom Line

Both single-shot and multi-shot gel injections work well for knee osteoarthritis. Research suggests a possible small advantage for 2-4 injection series, but the difference isn’t dramatic enough to override practical considerations.

Choose based on what matters most to you:

• If convenience is paramount, single-shot makes sense
• If you want the approach with the most research support, go with 3-shot
• If cost per visit matters most, multi-shot may be easier to manage

Most importantly, work with a skilled provider who uses proper injection technique—preferably with imaging guidance. The quality of the treatment often matters more than the specific protocol you choose.

Talk with your doctor about your priorities, check your insurance coverage, and make the choice that fits your life. Either way, you’re taking an important step toward better knee health.

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Last medically reviewed: January 15, 2025

Disclaimer: This article is for informational purposes only and does not replace professional medical advice. Always consult with a qualified healthcare provider about treatment options for your specific condition.