Expression of urotensin II (UII) is significantly elevated in the hearts of patients with congestive heart failure (CHF). Recent reports have also shown increased plasma levels of UII in patients with CHF, and these levels correlated with the severity of disease. We therefore hypothesized that blockade of UII signaling would improve cardiac function in a rat model of CHF. CHF was induced in rats by ligating the left coronary artery. Animals were randomized to either treatment with a specific UT receptor antagonist, SB-611812 (30 mg/kg/day, UID by gavage), or vehicle, starting either 30 min prior to coronary ligation (early treatment) or 10 days after ligation (delayed treatment). Treatment drug or vehicle was administered daily thereafter for 8 weeks. We measured cardiac function and evaluated the levels of mRNA expression for mediators of CHF. In addition, we evaluated UII and UT protein levels using immunohistochemistry and Western blotting. Cardiomyocyte hypertrophy was evaluated by measuring cardiomyocyte cross-sectional area. Animals with CHF showed increased UII and UT expression as evidenced by immunohistochemistry and Western blotting. Treatment with the SB-611812 significantly reduced overall mortality, left ventricular end-diastolic pressure by 72%, lung edema by 71%, right ventricular systolic pressure by 92%, central venous pressure by 59%, cardiomyocyte hypertrophy by 54%, and ventricular dilatation by 79% (P < 0.05). Therefore, blockade of the UT receptor reduced mortality and improved cardiac function in this model of myocardial infarction and CHF, suggesting an important role for UII in the pathogenesis of this condition.