Statins have been shown to be cardioprotective, however, their interaction with endogenous cardioprotection by ischemic preconditioning and postconditioning is not known. Here we have examined if acute and chronic administration of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor lovastatin affects the infarct size-limiting effect of ischemic preconditioning and postconditioning in rat hearts. Wistar rats were randomly assigned to three groups: i) vehicle-treated (1% methylcellulose p.o. for 12 days), ii) chronic lovastatin-treated (15 mg/kg/day p.o. for 12 days), and iii) acute lovastatin-treated (1% methylcellulose p.o. for 12 days and 50 µmol/L lovastatin in the perfusate) groups. Hearts isolated from the 3 groups were either subjected to a non-conditioning (aerobic perfusion followed by 30 min coronary occlusion and 120 min reperfusion, i.e. test-ischemia/reperfusion), preconditioning (3 intermittent periods of 5 min ischemia/reperfusion cycles before test-ischemia/reperfusion), or postconditioning (6 cycles of 10 s ischemia/reperfusion after test-ischemia) perfusion protocol. Preconditioning and postconditioning significantly decreased infarct size in vehicle-treated hearts. However, preconditioning failed to decrease infarct size in acute lovastatin-treated hearts but the effect of postconditioning remained unchanged. Chronic lovastatin treatment abolished postconditioning but not preconditioning, however, it decreased infarct size in the non-conditioned group. Myocardial levels of coenzyme Q9 were decreased in both acute and chronic lovastatin-treated rats. Western blot analysis revealed that both acute and chronic lovastatin treatment attenuated the phoshorylation of Akt, however, acute but not chronic lovastatin-treatment increased phosphorylation of p42 MAPK/ERK. We conclude that although lovastatin may lead to cardioprotection, it interferes with the mechanisms of cardiac adaptation to ischemic stress.