Recent studies have provided evidence that nocturnal cortisol secretion is coupled to ultradian rhythms of sleep. The present study was designed to specify how exogenous and sleep-related endogenous factors influence nocturnal adrenocorticotropin (ACTH) and cortisol secretion. We compared the influences of (1) temporary sleep deprivation, (2) arousals continuously induced during sleep and, (3) undisturbed sleep (baseline) on pituitary-adrenocortical activity in 10 healthy men. Sleep deprivation (DS) and continuous arousals during sleep (AS) were introduced at the beginning of the second rapid eye movement (REM) sleep period which is an epoch close to the first significant nocturnal rise in plasma cortisol. Compared with the baseline nights, plasma cortisol significantly increased immediately after continuous arousals were started or the subject was awakened and remained awake. Despite this exogenously provoked first cortisol peak, average cortisol release during DS and AS was no higher than during undisturbed sleep. The arousal-induced cortisol burst was followed by a temporary inhibition of cortisol secretion, suggesting that once the subject is aroused (i.e., in stage 1 sleep or awake), the hypothalamus-pituitary-adrenal (HPA) system becomes highly sensitive to negative feedback inhibition. Spontaneously occurring endogenous cortisol peaks of comparable size during undisturbed sleep did not exhibit such a temporary inhibition of cortisol secretion. We hypothesize that sleep attenuates negative feedback inhibition within the HPA system, whereas wakefulness (or stage 1 sleep) reflects increased feedback sensitivity of this system.