Administration of steroid hormones was demonstrated to modulate the sleep electroencephalogram (EEG) and sleep-associated hormonal secretion in specific ways. The present study was conducted to compare the effects of mifepristone (Mif), a mixed glucocorticoid (GR) and progesterone receptor (PR) antagonist, and megestrol acetate (Meg), a PR agonist. Nine healthy men were pretreated with either placebo or 200 mg Mif or 320 mg Meg, or a combination of both. Changes in plasma adrenocorticotropic hormone (ACTH), cortisol, and growth hormone concentrations were registered every 30 min; sleep EEG recordings were obtained continuously. Administration of Mif increased the morning plasma ACTH and cortisol surges, whereas Meg had the opposite effect. Growth hormone secretion was lowered by Mif pretreatment and enhanced by Meg. Simultaneous administration of both compounds led to largely compensated effects. The sleep EEG changes induced by Mif were a slight increase in the time awake and a delayed onset of slow-wave sleep. Meg led to a reduction of rapid-eye-movement sleep. Simultaneous administration of Mif and Meg showed a synergism in increasing time awake and shallow sleep: it therefore may be concluded that the sleep EEG effects are mediated by an interaction of GR and PR in unknown mechanisms.