Hypothalamic-pituitary-adrenal (HPA) axis activity was studied in 28 endogenously depressed, hospitalized patients. Measures of HPA activity obtained were baseline serum cortisol level, 24-hour urinary free cortisol excretion, and an overnight 2-mg dexamethasone suppression test. The patients then received double-blind and randomized treatment with imipramine hydrochloride, 150 mg daily, or amitriptyline hydrochloride, 150 mg daily, for four weeks. Four-week treatment response of all patients was compared with pretreatment HPA axis variables, and higher cortisol values after dexamethasone administration were found to be significantly correlated with greater improvement. There were no significant differences between imipramine and amitriptyline response, however, when improvement with each drug was compared with the pretreatment HPA variables.