Antivirals with proven effectiveness against the Omicron SARS-CoV-2 variant are required for COVID-19 treatment in hospitalized patients, particularly those with severe underlying conditions. Ensitrelvir, a 3C-like protease inhibitor, received emergency approval in Japan in November 2022, based on evidence of rapid symptom resolution in non-hospitalized patients, but confirmation of its effectiveness in hospitalized patients is lacking. This retrospective chart review reports outcomes for all patients who received ensitrelvir whilst hospitalized with SARS-CoV-2 infection at Rinku General Medical Center, Japan (November 2022-April 2023). Thirty-two hospitalized patients received 5 days of ensitrelvir treatment (375 mg loading dose, 125 mg as maintenance dose). Patients' mean age was 73.5 years and most had mild COVID-19. Patients exhibited various underlying diseases, most commonly hypertension (78.1%) and chronic kidney disease (25.0%). Seven (21.9%) patients were on hemodialysis. The most common concomitant medications were antihypertensives (59.4%) and corticosteroids (31.3%); 2 (6.3%) patients were being treated with rituximab; 28 (87.5%) patients had viral persistence following pre-treatment by remdesivir. Following ensitrelvir treatment, viral clearance was recorded in 18 (56.3%) patients by Day 6 and 25 (78.1%) patients at final measurement. All patients experienced clinical improvement as assessed by the investigator at Day 5. No intensive care unit admissions or deaths due to COVID-19 occurred. No new safety signals were observed. In conclusion, positive virological outcomes were observed following ensitrelvir treatment, in hospitalized patients with SARS-CoV-2 in a real-world setting, including high-risk patients, who failed previous antiviral therapy. These results require confirmation in more extensive studies. TRIAL REGISTRATION: UMIN000051300.