Abstract Background We measured T-cell and antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vaccinated patients hospitalized for coronavirus disease 2019 (COVID-19) and explored their potential value to predict outcomes. Methods This was a prospective, longitudinal study including vaccinated patients hospitalized with Delta and Omicron SARS-CoV-2 variants. TrimericS-IgG antibodies and SARS-CoV-2 T-cell response were measured using a specific quantitative interferon-γ release assay (IGRA). Primary outcome was all-cause 28-day mortality or need for intensive care unit (ICU) admission. Cox models were used to assess associations with outcomes. Results Of 181 individuals, 158 (87.3%) had detectable SARS-CoV-2 antibodies, 92 (50.8%) showed SARS-CoV-2–specific T-cell responses, and 87 (48.1%) had both responses. Patients who died within 28 days or were admitted to ICU were less likely to have both unspecific and specific T-cell responses in IGRA. In adjusted analyses (adjusted hazard ratio 95% confidence interval), for the entire cohort, having both T-cell and antibody responses at admission (0.16 .05–.58) and Omicron variant (0.38 .17–.87) reduced the hazard of 28-day mortality or ICU admission, whereas higher Charlson comorbidity index score (1.27 1.07–1.51) and lower oxygen saturation to fraction of inspired oxygen ratio (2.36 1.51–3.67) increased the risk. Conclusions Preexisting immunity against SARS-CoV-2 is strongly associated with patient outcomes in vaccinated individuals requiring hospital admission for COVID-19. Persons showing both T-cell and antibody responses have the lowest risk of severe outcomes. In this prospective study of vaccinated patients hospitalized for COVID-19, T-cell immunity against SARS-CoV-2 measured by interferon-γ release assay (IGRA) was strongly associated with patient outcomes. Persons showing both positive antibody test and T-cell responses by IGRA had the lowest risk of mortality.