Abstract: Objective: The objective was to determine if patients hospitalized with a primary medical diagnosis and any co-occurring serious mental illness (SMI) were more likely than patients without any co-occurring SMI diagnosis to experience a subsequent medical hospitalization.Method: This was a longitudinal cohort study of 925,705 adult persons (aged 18+ years). Patients hospitalized in Washington State from 2004 to 2008 were followed through 2009 (for an average of 43 months).Results: Compared to patients hospitalized for medical conditions without co-occurring SMI, patients with co-occurring dysthymia, bipolar and major depressive disorders were at an elevated risk for long-term subsequent hospitalization. Patients in the combined co-occurring mood disorders cohort were more likely (hazard ratio=1.13; 99% confidence interval=1.10–1.16; P<.001) than patients in the reference cohort to experience a subsequent medical hospitalization. A significant interaction between substance and mood disorders that increased risk for subsequent hospitalization was also observed.Conclusion: Hospitalized patients with co-occurring mood disorders are at high risk for repeat hospitalization for a medical reason. This high-risk population, including those with substance abuse, should be a focus of research efforts to identify and address ambulatory-care-sensitive conditions amenable to strategies that decrease complications and illness leading to subsequent hospitalizations.