Although symptom and viral rebound have been reported after nirmatrelvir-ritonavir treatment, the trajectories of symptoms and viral load during the natural course of COVID-19 have not been well described.To characterize symptom and viral rebound in untreated outpatients with mild to moderate COVID-19.Retrospective analysis of participants in a randomized, placebo-controlled trial. (ClinicalTrials.gov: NCT04518410).Multicenter trial.563 participants receiving placebo in the ACTIV-2/A5401 (Adaptive Platform Treatment Trial for Outpatients With COVID-19) platform trial.Participants recorded the severity of 13 symptoms daily between days 0 and 28. Nasal swabs were collected for SARS-CoV-2 RNA testing on days 0 to 14, 21, and 28. Symptom rebound was defined as a 4-point increase in total symptom score after improvement any time after study entry. Viral rebound was defined as an increase of at least 0.5 log10 RNA copies/mL from the immediately preceding time point to a viral load of 3.0 log10 copies/mL or higher. High-level viral rebound was defined as an increase of at least 0.5 log10 RNA copies/mL to a viral load of 5.0 log10 copies/mL or higher.Symptom rebound was identified in 26% of participants at a median of 11 days after initial symptom onset. Viral rebound was detected in 31% and high-level viral rebound in 13% of participants. Most symptom and viral rebound events were transient, because 89% of symptom rebound and 95% of viral rebound events occurred at only a single time point before improving. The combination of symptom and high-level viral rebound was observed in 3% of participants.A largely unvaccinated population infected with pre-Omicron variants was evaluated.Symptom or viral relapse in the absence of antiviral treatment is common, but the combination of symptom and viral rebound is rare.National Institute of Allergy and Infectious Diseases.