Background: Millions of people have now been vaccinated against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). However, it is still unclear which antibody levels provide protection against mortality. It is further unknown whether measuring antibody concentrations on hospital admission allows for identifying patients with a high risk of mortality. Objectives: To evaluate whether anti‐SARS‐CoV2‐spike antibodies on hospital admission predict in‐hospital mortality in patients with coronavirus disease 2019. Methods: We conducted a prospective, multicentre cohort study on 1152 hospitalized patients who tested positive for SARS‐CoV‐2 with a polymerase chain reaction–based assay. Patients were classified by vaccination status. Anti‐SARS‐CoV‐2 spike antibodies were determined on hospital admission. The investigated end point was in‐hospital mortality for any cause. Results: Spike antibodies on hospital admission were significantly lower in non‐survivors in both non‐vaccinated (73 U/ml, 95%CI 0–164 vs. 175 U/ml, 95%CI 124–235, p = 0.002) and vaccinated patients (1056 U/ml, 95%CI 701–1411 vs. 1668 U/ml, 95%CI 1580–1757, p < 0.001). Further, spike antibodies were significantly lower in fully vaccinated and boostered patients who died compared to those who survived (mean 883 U/ml, 95%CI 406–1359 vs. 1292 U/ml, 95%CI 1152–1431, p = 0.017 and 1485 U/ml, 95%CI 836–2133 vs. 2050 U/ml, 95%CI 1952–2149, p = 0.036). Patients infected with the currently prevailing Omicron variant were three times more likely to die if spike antibodies were <1200 U/ml (OR 3.458, 95%CI 1.562–7.656, p = 0.001). After adjusting for potential confounders, this value increased to an aOR of 4.079 (95%CI 1.809–9.198, p < 0.001). Conclusion: Anti‐SARS‐CoV2 spike‐antibody levels on hospital admission are inversely associated with in‐hospital mortality. Hospitalized patients with lower antibody levels have a higher risk of mortality. [ABSTRACT FROM AUTHOR]