Little is known about the course of affective illnesses in patients with diabetes or in other physically ill patients. We report a follow-up study of 37 diabetic adults with major depression (according to DSM-III), 28 (76%) of whom were located and reinterviewed 5 yr after the index evaluations. At follow-up, 18 (64%) of the 28 depressed patients had experienced an episode of major depression within the previous 12 mo; 12 of these patients satisfied diagnostic criteria for depression at the time of reevaluation. The 18 patients with recurrent depression had a mean of 4.2 depressive episodes over the 5-yr period. An additional 4 patients met criteria for current dysthymic disorder, bringing the number to 22 (79%) of the total patients ill with affective disorder during the 5-yr follow-up period. In contrast, the likelihood of symptomatic affective disorder was only 10% over the same follow-up period in a comparison group of diabetic subjects without depression at the index evaluation (P<.001). Occurrence of depressive episodes appeared independent of diabetes complications because both the depressed and comparison groups had similar rates of neuropathy, retinopathy, and nephropathy. These data suggest that the natural course of depression in diabetes is malevolent, possibly more so than depression in the medically well.