Renal function was monitored in 20 previously refractory hypertensive patients treated for 2--7 years with minoxidil, sympathetic suppressants, and diuretics. Serum creatinine concentration increased by more than 1 mg/dl in 9 of the 20 patients. In 4 of the 9 patients, renal disease progressed to require hemodialysis. Eleven patients had no progression of renal disease (creatinine increased less than or equal to 1 mg/dl). Three of the 11 had had malignant hypertension with renal failure which was reversed during this triple therapy. Neither the quality of blood pressure control nor the duration of minoxidil therapy correlated with increases in serum creatinine concentration. Plasma norepinephrine levels were higher (p less than 0.01) and plasma renin activity lower (p less than 0.02) in the group with progression of renal disease. Serum creatinine at the time when neuroendocrine studies were done correlated with PNE (r = 0.51, p less than 0.05). Addition of clonidine to this triple regimen in 2 patients with advanced renal disease lowered plasma norepinephrine by 63 and 81%. These findings suggest that the high norepinephrine levels are due to excess release of norepinephrine rather than defective renal elimination of this catecholamine. Whether the elevated plasma norepinephrine contributes to or is a result of the underlying disease is not known.