Objectives: Recent studies have shown that ischemic post-conditioning reduces myocardial ischemia-reperfusion (I/R) injury; however, the effects of inhibiting apoptosis on cardio-protection induced by ischemic postconditioning remain to be determined. The objective of this study was to investigate whether ischemic postconditioning attenuates myocardial I/R injury by reduced apoptosis in a closed-chest pig model of acute myocardial infarction. Methods: Diannan small-ear pigs were randomly divided into 3 groups (5/group): (1) The sham group underwent a sham operation without ischemia; (2) the I/R group received 60 minutes of ischemia and 72 hours of reperfusion; and (3) the ischemic postconditioning (Postcond) group was treated the same as the I/R group except that the pigs received 8 cycles of 30 seconds of reperfusion and 30 seconds of ischemia at the onset of reperfusion. After 72 hours of reperfusion, infarct size was measured by 2,3,5-triphenyltetrazolium chloride staining. Apoptotic cells in the peri-infarct myocardium were evaluated with the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method, and apoptosis-related molecules were studied with western blotting analysis. Results: After 72 hours of reperfusion, mean (+/- SEM) infarct size was significantly smaller in the Postcond group than in the I/R group (23.26% +/- 3.13% versus 10.89% +/- 2.02%, P < .05). Apoptotic myocytes in the peri-infarct region were lower in the Postcond group than in the I/R group (15.31% +/- 4.58% versus 33.83% +/- 4.44%, P < .05). This decrease in the extent of apoptosis was accompanied by a significant decrease in Bax expression (0.306 +/- 0.075 versus 0.433 +/- 0.102 for the I/R group; P < .05) and a significant increase in Bcl-2 expression (1.801 +/- 0.227 versus 1.267 +/- 0.308 for the I/R group; P < .05). Conclusions: In a clinically relevant closed-chest pig model of myocardial infarction, these data suggest the following: (1) Ischemic postconditioning reduces infarct size following prolonged reperfusion, and (2) this cardioprotective effect is likely achieved via antiapoptotic mechanisms.