The mineralocorticoid (MC) receptor antagonist spironolactone (SL) improves morbidity and mortality in patients with congestive heart failure (CHF). We tested the hypothesis that the central nervous system actions of SL contribute to its beneficial effects. SL (100 ng/h for 28 days) or ethanol vehicle (VEH) was administered intracerebroventricularly or intraperitoneally to rats with CHF induced by coronary artery ligation (CL) and to SHAM-operated controls. The intracerebroventricular SL treatment prevented the increase in sodium appetite and the decreases in sodium and water excretion observed within a week of CL in VEH-treated CHF rats. Intraperitoneal SL also improved volume regulation in the CHF rats, but only after 3 wk of treatment. Four weeks of SL treatment, either intracerebroventricularly or intraperitoneally, ameliorated both the increase in sympathetic drive and the impaired baroreflex function observed in VEH-treated CHF rats. These findings suggest that activation of MC receptors in the central nervous system plays a critical role in the altered volume regulation and augmented sympathetic drive that characterize clinical heart failure.