AbstractThe aim of this study was to analyze whether the coronavirus disease 2019 (COVID‐19) vaccine reduces mortality in patients with moderate or severe COVID‐19 disease requiring oxygen therapy. A retrospective cohort study, with data from 148 hospitals in both Spain (111 hospitals) and Argentina (37 hospitals), was conducted. We evaluated hospitalized patients for COVID‐19 older than 18 years with oxygen requirements. Vaccine protection against death was assessed through a multivariable logistic regression and propensity score matching. We also performed a subgroup analysis according to vaccine type. The adjusted model was used to determine the population attributable risk. Between January 2020 and May 2022, we evaluated 21,479 COVID‐19 hospitalized patients with oxygen requirements. Of these, 338 (1.5%) patients received a single dose of the COVID‐19 vaccine and 379 (1.8%) were fully vaccinated. In vaccinated patients, mortality was 20.9% (95% confidence interval [CI]: 17.9–24), compared to 19.5% (95% CI: 19–20) in unvaccinated patients, resulting in a crude odds ratio (OR) of 1.07 (95% CI: 0.89–1.29; p = 0.41). However, after considering the multiple comorbidities in the vaccinated group, the adjusted OR was 0.73 (95% CI: 0.56–0.95; p = 0.02) with a population attributable risk reduction of 4.3% (95% CI: 1–5). The higher risk reduction for mortality was with messenger RNA (mRNA) BNT162b2 (Pfizer) (OR 0.37; 95% CI: 0.23–0.59; p < 0.01), ChAdOx1 nCoV‐19 (AstraZeneca) (OR 0.42; 95% CI: 0.20–0.86; p = 0.02), and mRNA‐1273 (Moderna) (OR 0.68; 95% CI: 0.41–1.12; p = 0.13), and lower with Gam‐COVID‐Vac (Sputnik) (OR 0.93; 95% CI: 0.6–1.45; p = 0.76). COVID‐19 vaccines significantly reduce the probability of death in patients suffering from a moderate or severe disease (oxygen therapy).