Long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC), affects a significant portion of individuals who contract COVID-19, regardless of initial infection severity. With its broad and debilitating symptoms, from 'brain fog' to fatigue, the search for preventative strategies is crucial. Paxlovid, an oral antiviral approved for treating acute COVID-19 in high-risk patients, emerged as a potential contender for preventing long COVID by limiting viral replication during the initial infection. However, the evidence supporting its use for this purpose is complex and, at times, conflicting.
The Rationale Behind Paxlovid's Potential
Paxlovid works by inhibiting the main protease (Mpro) of the SARS-CoV-2 virus, which is a critical enzyme for viral replication. By blocking Mpro, Paxlovid essentially halts the virus's ability to create more copies of itself. This effectively reduces the overall viral load in the body, which is the amount of active virus present. The hypothesis linking this action to long COVID prevention is that persistent viral replication or viral reservoirs within the body may be a contributing factor to the development of lingering symptoms. Therefore, reducing the initial viral load early on could, in theory, mitigate the risk of long-term complications.
Divergent Research Findings
Research into Paxlovid's effect on long COVID has produced a range of outcomes, largely dependent on the study methodology and patient population. It's essential to differentiate between the findings from observational studies and those from randomized controlled trials (RCTs).
Findings from Observational Studies
Early observational studies, which analyze existing data without direct intervention, often suggested a protective effect. For example, a large retrospective study from the U.S. Department of Veterans Affairs (VA) system found that Paxlovid treatment during acute infection was associated with a 26% lower risk of developing long COVID over a six-month period. A more recent study from the NIH's RECOVER initiative, analyzing millions of patient records, found that Paxlovid reduced the risk of long COVID by 6% across the population studied and significantly more so for high-risk patients. This study also suggested a particular benefit for cognitive and fatigue-related symptoms. A separate RECOVER study found that Paxlovid reduced the rate of long COVID by nearly 3 events for every 100 high-risk people treated, though it found no significant benefit for low-risk individuals.
Findings from Clinical Trials
More rigorous clinical trials have presented a different picture. The Yale Paxlovid for Long COVID (PAX LC) Trial, a phase 2 RCT published in April 2025, investigated whether a longer, 15-day course of Paxlovid could help relieve existing long COVID symptoms. The trial found no significant difference in symptom improvement compared to a placebo group. While this was a treatment study and not a prevention trial, its results contribute to the broader skepticism about Paxlovid's role in PASC. A separate UCSF observational study published in January 2024 found no connection between Paxlovid treatment and long COVID symptoms in a vaccinated, non-hospitalized population, with some analysis even suggesting a possible association with rebound and long COVID symptoms.
The Role of Extended Dosing and Persistent Symptoms
Beyond prevention, some researchers and clinicians have explored using an extended course of Paxlovid to treat existing long COVID, hypothesizing that longer courses might eliminate viral reservoirs. A UCSF case series published in Communications Medicine in early 2025 documented 13 individuals with long COVID who took extended courses (7.5–30 days) of Paxlovid. The results were highly variable, with some patients reporting significant symptom reduction, others experiencing only temporary relief, and some seeing no benefit at all. These findings highlight the complex nature of long COVID and suggest that a one-size-fits-all approach to treatment is unlikely to succeed.
Limitations and Interpretation of the Data
Differences in study design, population demographics, the variant prevalent during the study period, and reliance on self-reported data all contribute to the conflicting results. Observational studies, while useful for showing real-world trends across large populations, are susceptible to confounding factors that are controlled for in randomized trials. For instance, people who are more proactive about their health or have better access to care may be more likely to receive Paxlovid and might have different underlying health trajectories. The complexity of long COVID, with its wide range of potential causes and hundreds of symptoms, also makes a single preventative treatment challenging. The scientific community continues to emphasize the urgent need for well-designed, large-scale randomized controlled trials to better understand Paxlovid's potential effects.
Key Studies on Paxlovid and Long COVID Risk
| Study | Study Type | Patient Population | Key Finding on Long COVID Risk | Limitations | Authoritative Source |
|---|---|---|---|---|---|
| VA Study (Al-Aly, 2022) | Retrospective Cohort | >56,000 veterans | 26% reduction in long COVID risk over 6 months; also reduced hospitalization and death risk. | Observational study, potential for confounding, study population mostly older men. | |
| RECOVER Initiative (Wang, 2025) | Retrospective Cohort (Target Trial Emulation) | >490,000 patients | 6% reduction in overall long COVID risk; greater benefit for high-risk patients. | Observational approach, EHR data limitations (e.g., adherence), reliance on diagnostic codes. | |
| Yale PAX LC Trial (Krumholz/Iwasaki, 2025) | Randomized Clinical Trial (RCT) | 100 participants | No significant effect on relieving existing long COVID symptoms in the cohort. | Focused on treatment, not prevention; small trial size; may not apply to initial infection. | |
| UCSF Study (Durstenfeld, 2024) | Observational Cohort | ~4,700 vaccinated, non-hospitalized patients | Found no association between Paxlovid treatment during acute infection and lower odds of long COVID. | Observational design, relies on self-reported symptoms, potential respondent bias. |
Conclusion
While some observational data offers a glimmer of hope that early Paxlovid treatment may help reduce the risk of long COVID, especially in older and high-risk individuals, the evidence is not conclusive. Other studies, particularly randomized controlled trials and large-scale observational studies in broader populations, have not demonstrated a reliable protective effect. Therefore, the current consensus is that Paxlovid is a valuable tool for preventing severe disease, hospitalization, and death in at-risk patients with acute COVID-19, but it is not a guaranteed preventative measure for long COVID. The field requires more robust clinical trials to clarify the drug's role and identify which patient subgroups might benefit most from its use in preventing long-term complications. In the meantime, healthcare providers should continue to prescribe Paxlovid based on its proven benefits for acute illness, while managing patient expectations regarding long COVID risk.
An authoritative source on ongoing long COVID research and treatment guidelines can be found at the National Institutes of Health (NIH).
