Bipolar disorder is a serious illness affecting approximately 2-4% of the population and is one of the world’s leading causes of disability. In individuals with bipolar disorder, medical comorbidity associated with cardiovascular, respiratory and endocrine disorders is related to increased rates of mortality. Recent updates to multi-system inflammatory related conceptualizations of bipolar disorder focus on the unique power that medical illness and biological processes may play as factors associated with course and outcome in bipolar disorder. The current study examined medical comorbidity and its associations with various demographic and psychological variables in individuals with bipolar disorder, schizophrenia, and major depressive disorder with psychotic features followed for 10 years from their first hospital admission. When compared to an age, gender and race-matched control sample from the population, those with bipolar disorder had significantly higher medical comorbidity across a range of medical diagnoses both at 6 months and 10 years after first hospital admission. Ten years following initial hospitalization, individuals in all three diagnostic groups reported increased rates of diabetes (OR: 2.0 – 3.7), stroke (OR: 4.6 – 7.0) and asthma (OR: 1.9 - 3.1), and individuals with bipolar disorder reported increased rates of cancer (OR = 2.1). A number of psychological and demographic symptoms were examined for their ability to predict the development of medical illness across the assessment interval. Overall rates of medical illness were elevated both early in illness course and 10 years after diagnosis, suggesting that broad sequelae of multi-system inflammation are present early and progress over time.