BACKGROUND: Despite effective vaccines and treatments for COVID-19, clinical burden persists. An unmet need exists for additional effective agents with safety profiles allowing use across a broad population. Ibuzatrelvir is an orally bioavailable SARS-CoV-2 Mpro inhibitor with demonstrated in vitro antiviral activity and low potential for safety concerns, including drug-drug interactions. METHODS: This phase 2b, double-blind, randomized clinical trial enrolled US adults aged 18 to <65 years with symptomatic COVID-19 and no risk factors for severe disease. Participants were randomized 1:1:2:2 to receive 100, 300, or 600 mg ibuzatrelvir or placebo orally twice daily for 5 days. Nasopharyngeal specimens were collected on days 1 (baseline), 3, 5, 10, 14, and 21; adverse events (AEs) were recorded through day 33. The primary end point was change in SARS-CoV-2 RNA level (viral load [VL]) from baseline to day 5 among participants with baseline VL ≥4 log10 copies/mL. RESULTS: Of 240 enrollees, 237 received ≥1 dose; 199 were included in the primary analysis. Placebo-adjusted least squares mean (80% confidence interval) change from baseline in VL (log10 copies/mL) at day 5 was significant across all doses: 100 mg, ‒0.7 (‒1.1 to ‒0.3) log10 copies/mL, P = .02; 300 mg, ‒0.8 (‒1.3 to ‒0.3), P = .01; and 600 mg, ‒1.2 (‒1.5 to ‒0.8), P < .0001. AEs occurred in similar percentages of participants across groups. No deaths from any cause or treatment-related serious AEs occurred through day 33, and no participants reported dysgeusia. CONCLUSIONS: All 3 ibuzatrelvir doses were associated with robust antiviral activity and an acceptable safety profile, supporting continued clinical development. CLINICAL TRIALS REGISTRATION: NCT05799495.