RU 486 [17 beta-hydroxy-11 beta-(4- dimethylaminophenyl )-17 alpha-(prop-1- ynyl )-estra-4,9-dien-3-one] is a new steroid analog which antagonizes glucocorticoid action at the receptor level in animals. To assess its potential antiglucocorticoid activity in man we studied the pituitary-adrenal response to RU 486 in normal men. The compound was administered at 0200 h and plasma cortisol and lipotropins (LPH) were measured hourly for 10 h. After 400 mg RU 486 significant and sustained elevation of both hormones occurred during the 0700-1200 h period: mean (+/- SE) plasma levels after placebo or RU 486 during this interval were, respectively, for cortisol (ng/ml), 63.4 +/- 8.2 and 112.7 +/- 2.9 (P less than 0.02); and for LPH (pg/ml), 34.8 +/- 11.3 and 71.6 +/- 15.4 (P less than 0.01). The 200- and 100-mg doses induced only transient cortisol and LPH increases. Administration of RU 486 (400 mg) at 1400 h induced no increase in plasma cortisol compared to placebo in the corresponding 2000 to 2400 h period. When RU 486 was administered concomitantly with dexamethasone (1 mg) at 2400 h, dose-dependent blockade of the dexamethasone-induced cortisol suppression at 0900 h was found (r = 0.62, P less than 0.01); this blockade was partial after the 100-mg dose, but complete after the 400-mg dose. Plasma LPH and ACTH showed parallel variations. We conclude that RU 486 antagonizes the negative pituitary feedback of both the nocturnal endogenous cortisol rise and exogenously administered dexamethasone. These actions are consistent with an antiglucocorticoid activity of this compound in man.