ATP-dependent potassium (K⁺_ATP) channels play a role in the infarct size-limiting effect of preconditioning in pigs. We previously demonstrated that preconditioning shortens monophasic action potential duration (MAPD) and accelerates the time to ventricular fibrillation (VF) during a prolonged ischemia in pigs. We sought to determine whether the mechanism of the reduced time to VF in preconditioned pigs is a consequence of K⁺_ATP channel activation. Pigs underwent 40 min of coronary occlusion and 2 h of reperfusion. Before this, animals received either no intervention (control), 10 min of ischemia and 10 min of reperfusion (preconditioned), or an intravenous infusion of nicorandil, a K⁺_ATP channel opener. Additional control, preconditioned, and nicorandil-treated pigs were pretreated by glibenclamide, an antagonist of K⁺_ATP channels. Because 1) the K⁺_ATP channel activator nicorandil did not produce shorter time to VF, 2) the K⁺_ATP channel inhibitor glibenclamide did not block the acceleration of VF by preconditioning, and 3) there was no relationship between time to VF and infarct size or MAPD, the major conclusion is that reduced time to VF in preconditioned animals is not a consequence of K⁺_ATP channel activation.