The present study has been designed to investigate the effect of Simvastatin, a 3-hydroxymethyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor, on ischemia-reperfusion (I/R)-induced myocardial injury. The isolated Langendorff-perfused rat hearts were subjected to global ischemia for 30 min followed by reperfusion for 120 min. Myocardial injury was assessed by measuring myocardial infarct size alongwith release of lactate dehydrogenase (LDH) and creatine kinase (CK) in the coronary effluent. Additionally, the oxidative stress parameters were analyzed in the heart which was assessed by measuring lipid peroxidation, superoxide anion generation and reduced glutathione. I/R was noted to produce myocardial injury, as assessed in terms of increase in myocardial infarct size, LDH and CK in coronary effluent. Moreover, oxidative stress was noted to be increased due to I/R injury as assessed in terms of decreased TBARS (thiobarbituric acid-reactive substance) and superoxide anion generation levels alongwith increase in reduced glutathione levels in the heart. Treatment with Simvatstain at different concenterations (3 μMol, 10 μMol and 30 μMol) afforded cardioprotection against I/R-induced myocardial injury in rat hearts as assessed in terms of reductions in myocardial infarct size, LDH and CK levels in coronary effluent. Moreover, the high degree of oxidative stress produced as a result of I/R injury was noted to be reduced by Simvastatin treatment. It may be concluded that reductions in myocardial infarct size and oxidative stress may be responsible for the observed cardioprotective potential of Simvastatin against I/R-induced myocardial injury.