Abnormal adrenocortical regulation has been reported in patients with endogenous depression, including excessive cortisol production with loss of circadian periodicity and decreased suppression by dexamethasone. The inhibitory effect of the neurotransmitter norepinephrine (NE) on the hypothalamic-pituitary adrenal (HPA) axis through the regulation of corticotropin-releasing factor has been suggested by animal in vitro studies. In this study of six normal human subjects we have examined the relationship of basal cortisol activity and its sensitivity to dexamethasone suppression, measured by 24-hr urinary free cortisol, with basal noradrenergic activity, diurnal variation, and response to postural stimulation, measured by plasma NE. Base-line cortisol and the degree of dexamethasone suppression were significantly inversely correlated with all base-line measures of NE response to stimulation. NE response to stimulation on the morning after dexamethasone was also inversely correlated with the degree of cortisol suppression. The increase in the morning NE response to stimulation after dexamethasone was inversely correlated with both base-line and suppressed cortisol levels. There is significant diurnal variation in stimulated NE activity after dexamethasone. There results are consistent with an inhibitory role for NE in the regulation of HPA system and a reciprocal effect for cortisol on noradrenergic activity. The implication of this relationship for the understanding of adrenocortical regulation in depression is discussed.