The 24-h profile of plasma ACTH and cortisol levels was determined in 18 men suffering from major depressive illness (8 with unipolar depression and 10 with bipolar depression) as well as in 7 age-matched normal men. Blood was sampled every 15 min. The circadian variation and episodic fluctuations were analyzed for each individual profile. Both unipolar and bipolar depressed patients had higher 24-h mean cortisol levels (P less than 0.01) than normal men, but no significant difference in 24-h mean ACTH level was found. The nadir of cortisol secretion occurred almost 3 h earlier in older normal subjects and patients with unipolar depression, regardless of age, than in younger normal subjects. This shift paralleled a similar advance of the ACTH nadir. Early timing of the quiescent period of ACTH-cortisol secretion was also found in several patients with bipolar depression, but did not reach significance at the group level. The hypercortisolism in the depressed patients was associated with an increase in the magnitude, but not the number, of cortisol secretory episodes. About 90% of the cortisol pulses could be related to a concomitant ACTH pulse in normal subjects as well as in both groups of depressed patients. However, concomitant ACTH and cortisol pulses were less correlated in magnitude in depressed patients than in normal subjects. These results indicate that major depressive illness is associated with disturbances of pituitary-adrenal function. The early timing of the nadir of ACTH-cortisol secretion suggests that disorders of circadian time keeping may characterize major endogenous depression.