OBJECTIVE This study evaluated the effect of digoxin on cardiac sympathetic activity in patients with congestive heart failure. BACKGROUND Digoxin favorably alters autonomic tone in heart failure. Whether it reduces cardiac sympathetic drive in the setting of heart failure is unknown. METHODS Digoxin (0.25 mg intravenously) was administered to 12 patients with severe heart failure and elevated left ventricular end-diastolic pressure (> 14 mm Hg, Group A), 5 patients with less severe heart failure who had normal left ventricular end-diastolic pressure (> 14 mm Hg, Group B) and 6 patients with normal ventricular function. Seven additional patients with heart failure were studied as a time control group. Cardiac and total body norepinephrine spillover, systemic arterial pressure, left ventricular filling pressure and peak positive first derivative of left ventricular pressure were all assessed before and 30 min after administration of digoxin. RESULTS In Group A there were no changes in hemodynamic variables or total body norepinephrine spillover after digoxin administration; however, there was a significant reduction in cardiac norepinephrine spillover (263 +/- 70 to 218 +/- 62 pmol/min, mean +/- SEM, p < 0.001). In contrast, in Group B, digoxin caused a significant increase in cardiac norepinephrine spillover that was not associated with any hemodynamic changes or a change in total body spillover. There were no hemodynamic changes or a change in total body spillover. There were no hemodynamic or spillover changes in the time control or normal ventricular function group. CONCLUSIONS Digoxin, in the absence of detectable inotropic or hemodynamic effects, caused a reduction in cardiac norepinephrine spillover in patients with heart failure who had elevated filling pressures. This finding suggests a potentially beneficial primary autonomic action of digoxin in patients with severe heart failure.