Abstract Objectives To assess the benefits of remdesivir in hospitalized COVID-19 patients receiving combined immunomodulatory therapy (CIT) with dexamethasone and tocilizumab. Methods This was a cohort study of microbiologically confirmed COVID-19 hospitalized patients. The primary outcome was all-cause 28 day mortality. Secondary outcomes were need for invasive mechanical ventilation (IMV) and IMV/death. Subgroup analyses according to SARS-CoV-2 cycle threshold (Ct) values and inflammation biomarkers were performed. Multivariable marginal structural Cox proportional hazards regression models were used to analyse the association between remdesivir therapy and the risk of outcomes of interest. Results Of 1368 hospitalized patients treated with corticosteroids, 1014 (74%) also received tocilizumab, 866 (63%) remdesivir and 767 (56%) tocilizumab + remdesivir. The 28 day mortality was 9% in the overall cohort, with an adjusted HR (aHR) of 0.32 (95% CI = 0.17–0.59) for patients receiving CIT. In the latter group, the 28 day mortality was 6.5%, with an aHR of 1.11 (95% CI = 0.57–2.16) for remdesivir use and there were no differences in secondary outcomes. The risk of primary and secondary outcomes with remdesivir differed by Ct and C-reactive protein (CRP) levels in patients receiving CIT: for 28 day mortality, the aHR was 0.48 (95% CI = 0.21–1.11) for Ct <25, 0.12 (95% CI = 0.02–0.66) for Ct <25 and <5 day symptom duration and 0.13 (95% CI = 0.03–0.50) for CRP <38 mg/L; for IMV and IMV/death, the aHR was 0.32 (95% CI = 0.13–0.77) and 0.33 (95% CI = 0.17–0.63), respectively, in patients with Ct <25. Conclusions The benefits of remdesivir administered with dexamethasone and tocilizumab in hospitalized COVID-19 patients differ depending on Ct and CRP. Remdesivir decreases the risk of mortality and need for IMV in patients with high viral loads and low-grade systemic inflammation.