Vasodilator drugs produce tachycardia and an increase in circulating plasma norepinephrine in normal subjects. In contrast, heart rate does not change when the same drugs are given to patients with congestive heart failure. To assess if this difference could be related to a different reflex activation of the sympathetic nervous system, the response of plasma norepinephrine to nitroprusside infusion and to head-up tilt was studied in 5 normal subjects and in 46 patients with chronic congestive heart failure. Norepinephrine and heart rate increased significantly during both stimuli in normal subjects but were unchanged during nitroprusside infusion for the entire group of patients with heart failure, with considerable variability in individual responses. In 21 patients (Group I) norepinephrine increased during nitroprusside infusion, while in the remaining 25 (Group II) norepinephrine decreased. The hemodynamic response to nitroprusside was similar in the two groups, thus suggesting that the different changes in plasma norepinephrine could not be explained on the basis of a different hemodynamic response to the drug. Plasma norepinephrine also did not change significantly in Group II during tilt, although the decrease in intracardiac pressure and the increase in peripheral resistance were similar to those in Group I who increased norepinephrine normally by 56%. These data indicate that a subset of patients with severe ventricular dysfunction have an abnormal humoral, reflex sympathetic response to changes in arterial or intracardiac pressure, or both. The higher mortality in Group II suggests that this alteration in the sympathetic response may be a marker of the severity and prognosis of heart failure.