This study explored the effect of elevated systemic cortisol levels on plasma epinephrine and norepinephrine, and hemodynamic variables, in patients with active Cushing's syndrome; ratings of depressed mood were also obtained. Norepinephrine levels were significantly negatively correlated with 24 h urinary free cortisol levels. Cushing's patients without depressed mood showed more robust negative correlations than those with depressed mood. The inverse relationship between norepinephrine and cortisol is consistent with data obtained previously in acute studies of normal subjects. Mechanisms which might explain these relationships include changes in control of catecholamine production, release, and or metabolic clearance in Cushing's patients. The decrease in the strength of association in depressed Cushing's patients is consistent with prior studies that suggest abnormal relationships between hypothalamic-pituitary-adrenocortical activity and noradrenergic function in major depressive disorder.