A 15-day course of nirmatrelvir-ritonavir (NMV/r) was evaluated in a randomized clinical trial (STOP-PASC) for its efficacy in reducing the severity of postacute sequelae of SARS-CoV-2 infection (PASC) symptoms in adults with moderate to severe symptoms lasting more than 3 months. The study involved 155 participants, most of whom had received the primary series of COVID-19 vaccination. Participants were randomly assigned to receive either NMV/r or placebo-ritonavir (PBO/r) twice daily for 15 days. The primary outcome was the pooled severity of six core PASC symptoms (fatigue, brain fog, shortness of breath, body aches, gastrointestinal symptoms, and cardiovascular symptoms) assessed at 10 weeks using a Likert scale. Secondary outcomes included symptom severity at various time points, symptom burden and relief, patient-reported outcomes, and physiological measures. The results showed no statistically significant difference in symptom severity between the NMV/r and PBO/r groups at 10 weeks. No significant differences were found in patient global impression scores, symptom burden, or changes in PROMIS measures. Adverse events were similar in both groups and mostly of low grade. The study found that NMV/r was generally safe but did not demonstrate significant benefit for improving PASC symptoms in a mostly vaccinated cohort with prolonged symptom duration. The findings suggest that further research is needed to determine the role of antivirals in the treatment of PASC. The study highlights the need for validated clinical endpoints and biomarkers for PASC research, as well as the importance of exploring combination therapies and adaptive trial designs to better understand the complex nature of PASC.A 15-day course of nirmatrelvir-ritonavir (NMV/r) was evaluated in a randomized clinical trial (STOP-PASC) for its efficacy in reducing the severity of postacute sequelae of SARS-CoV-2 infection (PASC) symptoms in adults with moderate to severe symptoms lasting more than 3 months. The study involved 155 participants, most of whom had received the primary series of COVID-19 vaccination. Participants were randomly assigned to receive either NMV/r or placebo-ritonavir (PBO/r) twice daily for 15 days. The primary outcome was the pooled severity of six core PASC symptoms (fatigue, brain fog, shortness of breath, body aches, gastrointestinal symptoms, and cardiovascular symptoms) assessed at 10 weeks using a Likert scale. Secondary outcomes included symptom severity at various time points, symptom burden and relief, patient-reported outcomes, and physiological measures. The results showed no statistically significant difference in symptom severity between the NMV/r and PBO/r groups at 10 weeks. No significant differences were found in patient global impression scores, symptom burden, or changes in PROMIS measures. Adverse events were similar in both groups and mostly of low grade. The study found that NMV/r was generally safe but did not demonstrate significant benefit for improving PASC symptoms in a mostly vaccinated cohort with prolonged symptom duration. The findings suggest that further research is needed to determine the role of antivirals in the treatment of PASC. The study highlights the need for validated clinical endpoints and biomarkers for PASC research, as well as the importance of exploring combination therapies and adaptive trial designs to better understand the complex nature of PASC.