The response to iv dexamehasone was studied in patients with chronic renal failure in whom resistance to suppression of plasma cortisol levels after oral steroid had been reported previously. One milligram of dexamethasone was given iv at 2300 h, and plasma cortisol levels were measured every 20 min between 0500-1000h in patients with renal failure, normal controls, and patients with pituitary-dependent Cushing's syndrome. Normal subjects showed a decrease in mean plasma cortisol levels to less than 3 micrograms/dl; patients with Cushing's syndrome showed no suppression of cortisol secretory activity during the sampling period. In renal failure patients, morning cortisol levels fell to values lower than those achieved when the 1-mg dose was given orally or when the steroid was not given, but did not suppress to the levels seen in normals. Early resumption of cortisol secretion occurred in four of five renal failure patients during the 6-11 h after dexamethasone administration. These studies show that iv dexamethasone is more effective than the oral steroid in suppressing pituitary-adrenocortical activity in renal failure patients. However, the incomplete suppression and early resumption of cortisol secretion which are present in chronic renal failure patients even after iv dexamethasone support the suggestion that they have disordered feedback control of the hypothalamic-pituitary-adrenocortical axis.