In situ hearts and isolated cardiomyocytes from heterozygous connexin 43-deficient (Cx43^+/−) mice cannot be protected by ischemic preconditioning or diazoxide. We have now addressed the role of connexin 43 in ischemic postconditioning (PC). Wild type (WT) and Cx43^+/−mice were subjected to 30 min coronary occlusion and 120 min reperfusion, with and without a PC protocol of three cycles of 10 s coronary occlusion/10 s reperfusion. Infarct size (TTC staining) was reduced by PC from 54±5 to 37±3% of area at risk in WT. Likewise, infarct size was reduced by PC from 53±4 to 34±3% of area at risk in Cx43^+/−. We conclude that connexin 43 is no prerequisite for PC’s protection. To this end, the signal transduction of ischemic preconditioning and postconditioning differs.