In this study mean 4 p.m. cortisol levels were significantly higher in patients with major depression than in control subjects or in patients with bipolar depression or dysthymic-related disorders. Moreover, the distribution of values differed significantly among groups. Eighteen of 45 patients with major depression had cortisol levels of 10 micrograms/dl or more, compared with 2 of 20 bipolar depressed patients and 0 of 31 controls. Patients with very high cortisol levels (15 micrograms/dl or more) tended to fulfill criteria for major depression with mood-congruent psychosis. The distribution of values in the major depression group also suggested the existence of three major subgroups. The authors discuss the implications of these data.