Previous studies have suggested that the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors attenuate ischemia-reperfusion injury by increasing the activity of endothelial nitric oxide synthase (eNOS). We assessed whether short-term treatment with atorvastatin reduces myocardial infarct size in the rat. Rats (male Sprague-Dawley) received atorvastatin 2 mg/kg per day (n=9), 10 mg/kg per day (n=8), or 75 mg/kg per day (n=11), or placebo (n=11) by gastric gavage for 3 days. Two additional groups received atorvastatin 10 mg/kg (n=7) or placebo (n=7) for 3 days and the nonselective nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), 15 mg/kg intravenously 15 min before surgery. All rats underwent 30 min of coronary artery occlusion followed by 180 min of reperfusion. Ischemic myocardium at risk was assessed with blue dye and infarct size by triphenyltetrazolium chloride. Ischemic myocardium at risk was comparable among groups. Infarct size, expressed as a percentage of the myocardium at risk, was significantly smaller in the atorvastatin 75 mg/kg group (22.6±2.8%; p =0.035 vs. placebo) and atorvastatin 10 mg/kg (20.3±3.8%; p=0.022 vs. placebo) compared with placebo (37.5±4.3%). The effect of atorvastatin 2 mg/kg was of smaller magnitude and did not reach statistical significance (infarct size 30.6±4.2% of the myocardium at risk). L-NAME abolished the protective effect of atorvastatin 10 mg/kg per day. Infarct size was 43.0±4.1% in the atorvastatin group and 39.4±3.3% in the placebo group (p=0.503). In conclusion, short-term (3 days) atorvastatin (10-75 mg/kg/d) significantly reduced myocardial infarct size. The protective effect was completely abolished by L-NAME, strongly suggesting that this protective effect is mediated via the nitric oxide synthase pathway.