Abstract: We tested our hypothesis that postischemic conditioning (PostC) is effective in salvage of ischemic skeletal muscle from reperfusion injury and the mechanism involves inhibition of opening of the mitochondrial permeability transition pore (mPTP). In bilateral 8 x 13 cm pig latissimus dorsi muscle flaps subjected to 4h ischemia, muscle infarction increased from 22±4% to 41±1% between 2-24h reperfusion, and remained unchanged at 48h (38±6%) and 72h (40±1%) reperfusion (p<0.05; n=4 pigs). PostC induced by 4 cycles of 30-sec reperfusion/reocclusion at the onset of reperfusion after 4h ischemia, reduced muscle infarction from 44±2% to 22±2% at 48h reperfusion. This infarct protective effect of PostC was mimicked by intravenous injection of the mPTP opening inhibitor Cyclosporin A or NIM811 (10 mg/kg) at 5 min before the end of 4h ischemia and was abolished by intravenous injection of the mPTP opener Atractyloside (10 mg/kg) at 5 min before PostC (p<0.05; n=4-5 pigs). PostC or intravenous Cyclosporin A injection at 5 min before reperfusion caused a decrease in muscle myeloperoxidase activity and mitochondrial free Ca²⁺ concentration and an increase in muscle ATP content after 4h ischemia and 2h reperfusion compared with the time-matched control. These effects of PostC were abolished by intravenous injection of Atractyloside at 5 min before PostC (p<0.05; n=6 pigs). These observations support our hypothesis that PostC is effective in salvage of ischemic skeletal muscle from reperfusion injury and the mechanism involves inhibition of opening of the mPTP.