Hypercortisolism is a frequent endocrine sign in major depression and cortisol is a well-known anti-insulinergic hormone. Impaired oral glucose tolerance has already been described in major depression. However, thus far no information is available on spontaneous, circadian insulin secretion in patients. We studied 26 depressed inpatients along with 33 age- and sex-matched controls. Blood samples were collected at 30-minute intervals over a period of 26 hours (h) for estimation of cortisol, insulin and glucose. No differences in 24 h mean-insulin and glucose concentrations were detectable despite significantly reduced caloric consumption in patients. At the second morning a strictly standardized test meal of 2125 kjoule was given. Insulin and glucose responses to the test meal were significantly increased in hypercortisolemic patients compared to controls. Hence, patients with major depression have an impaired insulin sensitivity.