Studies that have conducted quantitative analysis of the sleep electroencephalogram (EEG) have demonstrated decreased delta sleep in PTSD. Elevations in both hypothalamic (neurohormonal) and extrahypothalamic (neurotransmitter) corticotropin releasing factor (CRF) release is associated with decreased delta sleep activity. We present data from several studies examining the effect of metyrapone administration on the sleep EEG in PTSD and control subjects. Plasma ACTH, cortisol, and 11-deoxycorticol were obtained the morning following polysomnographic sleep recordings before and after metyrapone administration. Delta sleep was measured by period amplitude analysis. The results demonstrate: a) decreased delta sleep in male subjects with PTSD; b) metyrapone administration resulted in an activation of the sleep EEG and a robust decrease in quantitative delta sleep; c) the sleep and endocrine (increase in ACTH) responses to metyrapone were significantly decreased in PTSD in two different study samples; and d) the metyrapone-related disruption to sleep in both samples was predicted by the increase in ACTH measured the following morning. These findings strongly suggest that the delta sleep response to metyrapone is a measure of the brain response to a hypothalamic CRF challenge. The attenuated delta sleep and endocrine response to metyrapone challenge in PTSD is consistent with a model of enhanced negative feedback regulation or downregulation of CRF receptors in an environment of chronically increased CRF activity.