Depression in a common, life-threatening complication of Cushing's syndrome and may occur in several other endocrine disorders. It is not clear, however, whether distinct features pertain to hypercortisolism. We studied depression in Cushing's syndrome differentiating pituitary-dependent and pituitary-independent forms, its incidence compared to Graves' disease, and its appearance in the prodromal phase of both conditions. To 66 consecutive patients with Cushing's syndrome and 70 with Graves' disease, after treatment, a semistructured interview for depressive symptoms based on Paykel's clinical interview for depression was administered. In Cushing's syndrome, the response of depression to normalization of urinary cortisol levels was evaluated by Kellner's global rating method. There was a significant difference in the occurrence of depression (p < 0.001) between Cushing's syndrome (62%) and Graves' disease (23%). Depression appeared in the prodromal phase in 27% of patients with Cushing's syndrome and in 14% of those with Graves' disease, but the difference was not significant. In Cushing's syndrome, there were no significant differences in depression between patients with pituitary-dependent (n = 41) and pituitary-independent (n = 20) forms, or in their response to treatment. About 70% of patients fully recovered from their depression, whereas there was no substantial change in the others and even worsening in 2. Our findings in Cushing's syndrome and Graves' disease are in agreement with previous investigations using specific diagnostic criteria for depression. We found a tendency for this symptom to manifest in the prodromal phase of both illnesses. An endocrine etiology should be, therefore, considered in depressed patients not responding to standard psychiatric treatment.