ObjectiveThe association of serious mental illness (affective or non-affective psychotic disorders) with higher mortality in patients infected with acute coronavirus disease 2019 (COVID-19) has been suggested. Although this association remains significant after adjusting for medical comorbidities in previous studies, admission clinical status and treatment modalities should be considered as important confounding factors. MethodsWe aimed to assess whether serious mental illness is associated with in-hospital mortality, in patients with COVID-19 by adjusting for comorbidities, admission clinical status, and treatment modalities. Our nationwide cohort in Japan included consecutive patients admitted to 438 acute care hospitals for laboratory-confirmed acute COVID-19 from January 1, 2020 to November 30, 2021. ResultsOf 67,348 hospitalized patients (mean [standard deviation] age, 54 [18.6] years; 3891 [53.0%] female), 2524 patients (3.75%) had serious mental illness. In-hospital mortality was 282/2524 (11.17%) among patients with serious mental illness, while it was 2118/64,824 (3.27%) in other patients. In the fully adjusted model, serious mental illness was significantly associated with in-hospital mortality (odds ratio, 1.49; 95% CI, 1.27–1.72). E-value analysis confirmed the robustness of the results. ConclusionSerious mental illness remains a risk for mortality in acute COVID-19 after adjusting for comorbidities, admission clinical status, and treatment modalities. Vaccination, diagnosis, early assessment and treatment should be prioritized for this vulnerable group.