OBJECTIVE The benefits of antiviral treatment with remdesivir in hospitalized patients with COVID-19 remain controversial. Clinical analyses are needed to demonstrate which patient populations are most likely to benefit. METHODS In a retrospective monocentric analysis, patients with COVID-19 treated between July 1, 2020 and June 30, 2021 at Hospital St. Georg, Leipzig, Germany were evaluated. The primary endpoint was time to clinical improvement, and the secondary endpoint was 28-day mortality. Propensity score matching was used for the endpoint analysis. RESULTS A total of 839 patients were fully evaluated, 68% of whom received specific COVID-19 drug therapy. Remdesivir was used in 31.3% of the patients, corticosteroids in 61.7%, and monoclonal antibodies in 2.3%. While dexamethasone administration was the most common therapeutic approach during the second pandemic wave, combination therapy with remdesivir and corticosteroids predominated during the third wave. Cox regression analysis revealed that combination therapy was not associated with faster clinical improvement (median: 13 days in both matched groups, HR 0.97 [95% CI 0.77-1.21], P = 0.762). By contrast, 28-day mortality was significantly lower in the corticosteroid-remdesivir group (14.8% versus 22.2% in the corticosteroid group, HR 0.60 [95% CI 0.39-0.95], P = 0.03) in the low-care setting. This effect was also demonstrated in a subgroup analysis of patients with remdesivir monotherapy (n = 44) versus standard of care (SOC). CONCLUSIONS In COVID-19 patients with only mild disease (low-flow oxygen therapy and treatment in a normal ward) who received corticosteroids and/or remdesivir in addition to SOC, early administration of remdesivir was associated with a measurable survival benefit.