Is Paxlovid No Longer Effective? A Look at Current Evidence and Guidance

October 12, 2025 •

4 min read

Recent clinical data from 2025 highlights a diminished effect of Paxlovid in preventing hospitalization and death among vaccinated, older adults, contrasting with its initial high efficacy. This shift prompts a re-evaluation of its role and effectiveness, leading many to ask: is Paxlovid no longer effective?

Quick Summary

While highly effective in initial unvaccinated trials, recent research shows Paxlovid's benefit against severe illness is less pronounced in vaccinated populations. The antiviral remains a key tool for high-risk individuals, though recent studies indicate limited effect on long COVID.

Key Points

Paxlovid is Still Effective for High-Risk Patients: Despite a different impact in a post-vaccine world, Paxlovid remains a critical tool for preventing severe illness, hospitalization, and death in high-risk individuals.
Effectiveness Varies by Immunity and Risk Status: The high efficacy seen in initial trials on unvaccinated patients does not directly translate to vaccinated, lower-risk populations, where the benefits are less pronounced.
No Significant Effect on Long COVID: Recent 2025 studies from Yale and other institutions indicate that Paxlovid is not effective at preventing or treating symptoms of long COVID.
Mechanism is Resistant to Variants: Paxlovid's mechanism of action, which targets a conserved protease, means it remains effective against current and evolving Omicron subvariants.
Important Considerations for Treatment: Potential drug-drug interactions, the phenomenon of viral rebound, and rare resistance mutations in immunocompromised individuals must be considered by healthcare providers.
Optimal Use Requires Timely Treatment: Like other antivirals, Paxlovid must be started within five days of symptom onset to be most effective at preventing severe disease.

Understanding the Paxlovid Mechanism

First approved in late 2021 and fully authorized in 2023 for certain adults, Paxlovid is a combination of two oral antiviral medications: nirmatrelvir and ritonavir. The primary active ingredient, nirmatrelvir, is a protease inhibitor designed to block a key enzyme (Mpro) that the SARS-CoV-2 virus needs to replicate. Ritonavir, historically used for HIV, acts as a 'booster' by slowing down the metabolism of nirmatrelvir in the liver, allowing it to stay in the body at effective concentrations for longer. This mechanism, which targets a non-spike protein part of the virus, is considered relatively robust against the constant evolution of new variants.

The Shifting Landscape of Effectiveness: Initial Trials vs. Current Data

The perception of Paxlovid's effectiveness has evolved significantly since its introduction. Early clinical trials during the pre-Omicron era showed impressive results. One Phase 2/3 study demonstrated an 89% reduction in the risk of COVID-related hospitalization or death in unvaccinated, high-risk patients who took the drug within three days of symptom onset. These findings solidified its role as a crucial tool for preventing severe disease.

However, the landscape changed with the dominance of Omicron variants and widespread vaccination. Subsequent real-world data and clinical studies from 2024 and 2025 have provided a more nuanced picture:

For vaccinated older adults, new UCLA-led research published in February 2025 found that Paxlovid did not significantly reduce hospitalization and mortality rates. This suggests the protective effect of widespread vaccination and prior immunity blunts some of the dramatic benefits observed in the earlier, unvaccinated trials.
For high-risk individuals, regardless of vaccination status, Paxlovid continues to be effective in preventing severe outcomes. An NIH-backed study published in early 2025, analyzing data up to August 2023, found Paxlovid reduced the risk of hospitalization by 39% and death by 61%, even among vaccinated patients. The benefit was particularly pronounced in those aged 65 and over.
For low-risk, vaccinated individuals, a 2024 study in the New England Journal of Medicine suggested Paxlovid might not offer significant symptom-relief benefits.

Efficacy Against Modern Variants and Long COVID

The core mechanism of Paxlovid's action—targeting a protease rather than the spike protein—is a key reason for its continued relevance. Lab data indicates that Paxlovid remains effective at neutralizing the SARS-CoV-2 virus even against recent Omicron subvariants like XBB.1.5 and BQ.1. This variant-proof aspect is a significant advantage over other treatments like monoclonal antibodies, many of which became ineffective as the virus mutated.

For many, the question extends beyond acute illness to the potential of preventing or treating long COVID. Here, the evidence is less promising. Studies published in 2025 from Yale and UCSF indicated that a standard or extended course of Paxlovid did not alleviate persistent symptoms of long COVID. While some very early observational data hinted at a mild protective effect for long COVID in older adults, the overall consensus is that Paxlovid is not a reliable preventive measure for this condition.

Concerns and Considerations

While generally well-tolerated, Paxlovid has several important considerations:

Drug-Drug Interactions: Ritonavir can interact with numerous other medications, including statins, blood thinners, and some anti-rejection drugs, potentially leading to serious complications. A full medication review with a healthcare provider is essential before starting treatment.
Viral Rebound: Some individuals experience a temporary return of COVID-19 symptoms or a positive test result a few days after completing their 5-day course. While this has been observed in both treated and untreated patients, research continues to investigate its significance. Extended Paxlovid courses are being explored for specific populations to reduce rebound risk.
Antiviral Resistance: Resistance mutations to Paxlovid's active ingredients are rare and appear to come with a significant fitness cost to the virus, limiting their widespread transmission. However, the emergence of resistance has been documented, particularly in immunocompromised patients with persistent infections.

Comparison of Paxlovid Effectiveness Across Patient Groups


Patient Group	Effect on Severe Disease/Death	Effect on Long COVID	Effect on Symptom Duration	Key Findings Summary
High-Risk & Unvaccinated	High reduction (89% in early trials)	Likely minimal	Reduces duration	Extremely effective in preventing severe illness and death.
High-Risk & Vaccinated	Moderate reduction (61% reduction in death, 39% in hospitalization)	Likely minimal	Mixed data; may not be significant	Remains beneficial for preventing severe illness, especially in older patients.
Low-Risk & Vaccinated	Likely minimal to no significant reduction	Negligible	Not significant compared to placebo	Provides little to no measurable benefit in preventing severe illness or long COVID.
Immunocompromised	Retains effectiveness; extended courses may be beneficial	Studies still developing; resistance emergence possible	Mixed data	Considered a valuable tool, but vigilance for resistance is needed.
Adolescents	Authorized under EUA for high-risk 12+	No effect seen in recent adolescent studies	Mixed data	Use is generally limited to higher-risk teens as per FDA guidance.

Conclusion: The Evolving Role of Paxlovid

To answer the question, 'Is Paxlovid no longer effective?': No, it is still an effective and critical tool in the fight against COVID-19, but its role has evolved. The widespread immunity from vaccination and prior infection has altered the benefit profile for certain patient groups. Paxlovid remains a highly recommended treatment for high-risk individuals—especially those aged 65 and older—where it can significantly reduce the risk of hospitalization and death.

For low-risk, vaccinated individuals, the benefit appears minimal, and it is not a solution for preventing or curing long COVID. The ongoing battle with a constantly mutating virus necessitates a personalized approach to treatment, emphasizing early intervention for those most vulnerable. As clinical evidence continues to accumulate, treatment guidelines are refined to ensure the right patients receive the most effective care at the right time.

For more information on outpatient COVID-19 treatment, you can visit the CDC's clinical guidance.

Frequently Asked Questions

Yes, Paxlovid is still an effective and recommended treatment for COVID-19, particularly for high-risk individuals. However, its benefit in reducing severe illness is less dramatic in vaccinated populations compared to initial trials on unvaccinated participants.

Paxlovid is indicated for adults and high-risk adolescents (12+ and 88+ lbs) with mild-to-moderate COVID-19 who are at high risk for progressing to severe disease, hospitalization, or death. This includes individuals over 50 and those with underlying health conditions, regardless of vaccination status.

Yes, laboratory data and real-world studies show that Paxlovid's mechanism of action remains effective against new Omicron subvariants, as it targets a part of the virus that is less prone to mutation than the spike protein.

Recent studies in 2025 have found little evidence that Paxlovid is effective at preventing or treating long COVID symptoms, even with extended courses.

The initial high efficacy was based on trials with unvaccinated individuals. With high rates of vaccination and prior infection, many people have some baseline immunity, meaning the additional protective benefit of Paxlovid is less dramatic.

Paxlovid can have serious interactions with many common medications, including statins, blood thinners, and some heart rhythm drugs. It is critical to provide your healthcare provider with a complete list of your medications before starting Paxlovid.

Yes, even if you are up-to-date on your COVID-19 vaccinations, you can and should take Paxlovid if you are at high risk for severe disease. The drug can offer additional protection, especially for older individuals and those with comorbidities.