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Since the beginning of coronavirus disease 2019 (COVID-19), several therapies have been purposed. Remdesivir has emerged as an encouraging antiviral drug with for the treatment of severe patients with documented COVID-19-related pneumonia. Although several studies about remdesivir effectiveness exist, no study investigated the combination of remdesivir with the vaccination status. The aim of this study was to assess if the administration of remdesivir could show some differences in outcomes on the basis of the vaccination status. The primary outcome was the mortality at hospital. The secondary outcomes of interest were the necessity of transfer to ICU and the need for oxygen supplementation. This is a retrospective longitudinal cohort study including all adult patients hospitalized for severe COVID-19 at the Padua University Hospital (Italy), between September 1, 2020, and January 31, 2022, and who received remdesivir. Baseline characteristics of the population according to vaccination status were given. To have a better estimate of the outcomes of interest, a propensity score of being vaccinated was performed. A total of 708 patients were included. A total of 605/708 patients (85.4%) completed the vaccination schedule. Overall, in-hospital mortality was 5.1% (n = 36), while 30-day mortality was 2.4% (n = 17). After propensity score matching, mortality between the two groups remained similar. The need for ICU and oxygen supplementation was lower in the vaccinated group. Our finding suggests that a complete vaccination course could have an impact in reducing the need for transfer in ICU and for high-flow therapy in moderate-to-severe COVID-19 patients treated with remdesivir.