The present two experiments were designed to investigate the effects of a synthetic and of a natural corticosteroid on nocturnal sleep in humans. Both experiments were held double-blind and designed according to a within-subject cross-over comparison. In the first experiment, 1 mg of dexamethasone applied orally prior to sleep (11.00 p.m.) led to a reduction of the percent of time spent in REM and in stage 4 sleep. The amount of stage 2 sleep tended to be increased after dexamethasone. In the second experiment, an infusion of 100 mg hydrocortisone throughout the night also reduced REM, but increased stage 4 sleep. A statistical comparison of both experiments suggested that both steroids not only reduced REM sleep but also tended to enhance intermittent wakefulness. This analysis also confirmed opposite effects on measures of slow-wave sleep of both substances. The results represent a first demonstration of differential effects of synthetic and natural corticosteroids on sleep, which has to be substantiated in further studies directly comparing effects of these steroids.