Postconditioning (POC) reduces lethal reperfusion injury under normal conditions, but its effectiveness under certain pathological states is in dispute. In the present study, we sought to determine the effect of chronic simvastatin treatment in hyperlipidemic animals with or without POC. Anesthetized rabbits were randomized into eight groups, as follows, and were subjected to 30-min myocardial ischemia followed by 3-h reperfusion. Normally fed animals: a Control group with no additional intervention, a Sim group treated with simvastatin for 3 weeks at a dose of 3 mg kg(-1), a POC group subjected to POC with eight cycles of 30-s ischemia/reperfusion, a Sim-POC group treated with simvastatin, and POC. Cholesterol fed (6 weeks) animals: a Chol group with no additional interventions, a Chol-Sim group treated with simvastatin for 3 weeks, a Chol-POC group subjected to POC, and a Chol-Sim-POC group treated with simvastatin and POC. Infarct size and plasma levels of malondialdehyde (MDA), nitrotyrosine (NT), NOx, total cholesterol, and LDL were evaluated. In a second series of experiments, heart tissue samples were taken for MDA, NT, and NOx assessment. Infarct size, circulating MDA, NT, NOx and cardiac MDA, NT, and NOx levels declined in POC and all Sim groups compared with Control, Chol, and Chol-POC (p < 0.05). Simvastatin also reduced total cholesterol and LDL plasma levels. In conclusion, a 3-week simvastatin treatment limits the infarct size and attenuates the oxidative and nitrosative stress both in normo- and in hyper-cholesterolemic rabbits subjected to ischemia-reperfusion irrespective of the presence of POC, while POC is effective only in normocholesterolemic animals.