INTRODUCTION: Ensitrelvir, a novel oral 3C-like protease inhibitor targeting severe acute respiratory syndrome coronavirus 2, has been available in Japan since November 2022. This report presents patient characteristics and treatment outcomes of patients receiving ensitrelvir with comparison to remdesivir during the same period. METHODS: A single-center chart review was conducted at Rinku General Medical Center, one of four designated medical institutions for specific infectious diseases in Japan. All hospitalized patients with coronavirus disease 2019 (COVID-19) between November 2022 and August 2024 who received either ensitrelvir or remdesivir in accordance with the on-label dosage and administration were included in the review. Information on patient background, severity of COVID-19, mortality after initiation of either treatment, post-treatment virologic outcomes, and clinical outcomes were collected from electronic records. Day 28 mortality, time to discharge, and time to viral clearance were calculated with and without adjustment using the inverse probability of treatment weighting (IPTW) method. RESULTS: During the study period, 156 patients received ensitrelvir and 337 received remdesivir as initial treatments, with average ages of 76.8 and 75.7 years, respectively. For baseline severity, 24.4% of ensitrelvir recipients and 50.7% of remdesivir recipients had moderate to severe COVID-19. All-cause mortality at day 28 was 1.9% for ensitrelvir and 5.9% for remdesivir and the hazard ratio was 0.32 (95% CI 0.09-1.07). All-cause mortality after IPTW adjustment was 3.8% and 5.7%, respectively, and the hazard ratio was 0.66 (95% CI 0.19-2.29). Time to discharge was shorter with ensitrelvir, and viral clearance was similar between groups. CONCLUSION: Ensitrelvir demonstrated a low day 28 mortality, even among patients with advanced age, immunosuppressive conditions, and moderate to severe COVID-19. These findings may suggest a potential role for ensitrelvir in the treatment of hospitalized patients with COVID-19. TRIAL REGISTRATION: This study was registered in UMIN Clinical Trials Registry (study ID UMIN000056047).