Background: Ischemic Postconditioning (IPC) reduces ischemia/reperfusion (I/R) injury under normal conditions. HMG-CoA reductase inhibitors (statins), which inhibit the synthesis of mevalonate, can interfere with the cardioprotective effect of IPC. However, the beneficial role of IPC in hyperlipidemic patients, post-acute administration of statins remains unknown. This study was to determine if acute administration of atorvastatin affect the infarct size-limiting effect of IPC in hyperlipidemic rats. Results: Compared to control group, infarct size decreased more significantly in atorvastatin+ IPC and atorvastatin+ IPC+ wortmannin groups than IPC or atorvastatin+ IPC+ PD98059 groups. Phosphorylation of PI3K/Akt was attenuated in atorvastatin + IPC+ wortmannin group, phosphorylation of P42 MAPK/ERK was increased in atorvastatin+ IPC and atorvastatin+ IPC+ wortmannin groups. Materials and Methods: Ninety four-weeks old male SD rats fed with cholesterol enriched diet for six weeks were randomized into nine groups (n = 10/group) sham group, control group, IPC group, atorvastatin group, wortmannin group, PD98059 group, atorvastatin+ IPC group, atorvastatin+ IPC+ wortmannin group and atorvastatin+ IPC+ PD98059 group. Atorvastatin was administered orally 12 hours before myocardial reperfusion. Conclusions: Post-translational activation of P42 MAPK/ERK, rather than PI3K/Akt, participates in the net protective effect of IPC and atorvastatin in hyperlipidemia.