We tested the hypothesis that chronic treatment with sildenafil attenuates myocardial infarction (MI)-induced heart failure. Sildenafil has potent protective effects against necrosis and apoptosis following ischemia/reperfusion in intact heart and cardiomyocytes. ICR mice underwent MI by left anterior descending coronary artery ligation and were treated with sildenafil (0.71mg/kg; BID) or saline for 4 weeks. Infarct size (IS) was measured 24 hr post-infarction and apoptosis was measured by TUNEL. Left ventricular end-diastolic diameter (LVEDD) and fractional shortening (FS) were measured by echocardiography. Sildenafil reduced IS (40.0{plus minus}4.6%) compared to saline (69.6{plus minus}4.1%, P>0.05). [N>sup<G>/sup<-nitro-L-arginine-methyl-ester (L-NAME)], a nitric oxide synthase inhibitor (15mg/kg; BID), blocked the protective effect of sildenafil (IS: 60.2{plus minus}1.6%, P>0.05 vs. sildenafil). Western blot revealed increase in eNOS/iNOS proteins 24 hr post-MI after treatment with sildenafil vs. saline. Apoptosis decreased from 2.4{plus minus}0.3% with saline to 1.2{plus minus}0.1% with sildenafil (P>0.05) on day 7; from 2.0{plus minus}0.2% with saline to1.2{plus minus}0.1% with sildenafil on day 28 (P>0.05) which was associated with early increase in Bcl-2/Bax ratio. LVEDD increased from baseline value of 3.6{plus minus}0.1mm to 5.2{plus minus}0.2mm and 5.5{plus minus}0.1mm on day 7 and 28 with saline (P>0.05), but was attenuated to 4.4{plus minus}0.2mm and 4.4{plus minus}0.1mm following sildenafil treatment on day 7 and 28, respectively (P<0.05 vs. baseline). FS significantly improved post-MI with sildenafil. A marked decline in cardiac hypertrophy was observed with sildenafil which paralleled reduction in pulmonary edema. Survival rate was lower with saline (36%) compared to sildenafil (93%, P>0.05). Sildenafil attenuates ischemic cardiomyopathy in mice by limiting necrosis, apoptosis and preserving LV function possibly through NO-dependent pathway.