We investigated ACTH and cortisol responses after ovine CRF injection (1 microgram/kg one bolus) in a group of 11 drug-free patients suffering from major depression. When compared to sex- and age-matched normal controls, our depressed patients showed: Higher ACTH basal values (p less than 0.002); higher cortisol basal values (p less than 0.009); blunted ACTH response to oCRF administration (p less than 0.23); higher cortisol response to oCRF (p less than 0.001). Our data show that in depressed patients the feed-back mechanism is functionally intact at the pituitary level on one hand, while on the other, a hyperresponsiveness of adrenal cortex (even to minimal stimuli) seems to be present. Moreover, a hypersecretion of endogenous CRF in these patients seems to be likely.