BACKGROUND: Coronavirus disease 2019 (COVID-19) remains a major public health concern, with continued resurgences of cases and substantial risk of mortality for hospitalized patients. Remdesivir has become standard-of-care for hospitalized COVID-19 patients. Given the continued evolution of the disease, clinical management of COVID-19 relies on evidence from the current endemic period. METHODS: Using the PINC AI Healthcare Database, remdesivir effectiveness was evaluated among adults hospitalized with primary diagnosis of COVID-19 between December 2021 and February 2024. Three cohorts were analyzed: adults (≥18 years), elderly (≥65 years), and those with documented COVID-19 pneumonia. Analyses were stratified by oxygen requirements. Patients who received remdesivir were matched to those who did not receive remdesivir using propensity score matching. Cox proportional hazards models were used to examine in-hospital mortality. RESULTS: 169 965 adults hospitalized for COVID-19 were included, of whom 94 129 (55.4%) initiated remdesivir in the first 2 days of hospitalization. Remdesivir was associated with significantly lower mortality rate compared to no remdesivir among patients with no supplemental oxygen charges (adjusted HR [95% CI]: 14-day, 0.75 [.69-.82]; 28-day, 0.77 [.72-.83]) and those requiring supplemental oxygen: 14-day, 0.76 [.72-.81]; 28-day, 0.79 [.74-.83]; P < .0001 for all). Similar findings were observed for elderly patients and those hospitalized with COVID-19 pneumonia. CONCLUSIONS: This evidence builds on what has been learned from randomized controlled trials from the pandemic era to inform clinical practices. Remdesivir was associated with significant reduction in mortality for hospitalized patients including the elderly and those with COVID-19 pneumonia.