Recent research suggests that affective disorder is associated with increased mortality and physical morbidity, but the reasons for this association remain uncertain. This report describes a 50-year prospective study of 240 men evaluated from the time they were university students in 1940–1942. A family history of mental illness was obtained and the men's habits, psychological adjustment, and marital and occupational satisfaction were followed every 2 years and their objective physical health was tracked every 5 years until age 70. Twenty-five men were identified as having affective spectrum disorder prior to age 53. Of the variables studied, the presence of affective spectrum disorder was the most powerful predictor of poor psychosocial outcome at age 65 and one of the most powerful predictors of poor physical health. Alcohol abuse and cigarette abuse accounted for the observed increased rates of heart disease and cancer. When alcohol abuse, smoking, and suicide were controlled for, affective disorder made a significant contribution to physical morbidity by age 70, but not to mortality from natural causes. Affective spectrum disorder, even in an educated population without antisocial trends, carries a profound negative risk to late-life physical and social adjustment.