Continuous evaluation of real-world treatment effectiveness of COVID-19 medicines is required due to the ongoing evolution of SARS-CoV-2 and the possible emergence of resistance. Therefore, this study aimed to analyze the outcomes in patients hospitalized with COVID-19 during the pandemic waves dominated by Delta and Omicron variants and treated with remdesivir (RDV) (n=762) in comparison to the demographically and clinically matched group not treated with any antivirals (n=1060). During the Delta wave, the RDV-treated group revealed 2-fold lower mortality (10.8 vs. 23.2%, p<0.001) and 1.5-fold lower during the Omicron-dominated period (11.4 vs. 16.8%, p=0.05). RDV-treated groups were characterized by a lower percentage of patients requiring mechanical ventilation, but the difference was not statistically significant. This study is the first real-world evidence that RDV remains effective during the dominance of more pathogenic SARS-CoV-2 variants and those that cause a milder course of the disease and continues to be an essential element of COVID-19 therapy.