Nirmatrelvir-ritonavir was developed for the treatment of COVID-19 and has shown efficacy in a Phase 2/3 study of high risk patients (EPIC-HR1). Monitoring for the emergence of viral resistance and recurrence of symptoms is a critical component of any antiviral drug development. As part of the study of viral resistance, a sub-analysis was conducted to examine viral load rebound (VLR) following nirmatrelvir-ritonavir treatment in the EPIC-HR study. Nasopharyngeal or nasal swabs were collected from all study participants at Day 1, Day 3, Day 5, Day 10, and Day 14, and analyzed for viral RNA load and next generation viral sequencing. Two categories of viral load rebound were considered including present/persistent and transient. In EPIC-HR, the proportion of present/persistent VLR was low, occurring at 1.73%(17/980) vs 2.32%(23/990) and for transient VLR 2.35%(23/980) vs 4.65%(46/990) in placebo vs nirmatrelvir-ritonavir participants, respectively. VLR occurred in both treatment arms and was not associated with low nirmatrelvir exposure, hospitalization or death, severe symptom relapse, serological status, or Mpro gene/cleavage treatment emergent mutations. In summary, viral load rebounds are likely a phenomena COVID-19 disease course and nirmatrelvir-ritonavir continue to be an important treatment option for high risk COVID-19 patients.