This study addresses the question of whether pituitary peptides (ie, beta-endorphin) show regulatory disruption in endogenous depression and, if so, does it co-occur in the same subjects who show cortisol dysregulation. Endogenously depressed patients and psychiatric controls from three centers were evaluated, when not taking medications, and studied for plasma cortisol and beta-endorphin levels. Plasma samples were taken at four time points over one hour, on the basal day, and 16 hours after 1 mg of dexamethasone. From 33% to 69% of the endogenous patients were abnormal in their postdexamethasone cortisol levels, and from 50% to 69% were abnormal on postdexamethasone beta-endorphin values (vs 0% and 8%, respectively, for controls). When endogenous subjects were evaluated for abnormality on both cortisol and beta-endorphin, after dexamethasone, it was found that the two measures of hypothalamic-pituitary-adrenal dysfunction did not necessarily co-vary. In fact when having either abnormal beta-endorphin or cortisol levels (or both) was used as a biological marker a larger number of the endogenous patients were detected than with either measure alone. Our conclusions are as follows: Plasma beta-endorphin shows a circadian rhythm similar to that seen with corticotropin (ACTH) and is suppressable by dexamethasone. In many endogenous patients plasma beta-endorphin levels escape from dexamethasone suppression. Many of these subjects are not cortisol escapers. When abnormality of either the beta-endorphin or cortisol is considered it is clear that both levels of the hypothalamic-pituitary-adrenal axis can be dysregulated in endogenous depression.