Preconditioning with ischemia delays lethal cell injury in ischemic myocardium. This study investigated whether multiple brief ischemic episodes could protect the heart from a subsequent sustained ischemic insult. Two experiments were conducted: one with 40-minute occlusions and another with 3-hour occlusions. In the 40-minute study, preconditioning with four 5-minute ischemic episodes reduced infarct size to 25% of that in control animals (p < 0.001). In the 3-hour study, infarct sizes were similar between preconditioned and control groups. The protective effect in the 40-minute study may have been due to reduced ATP depletion and/or catabolite accumulation during sustained ischemia. These results suggest that multiple brief ischemic episodes, often preceding myocardial infarction in humans, may delay cell death after coronary occlusion, allowing greater myocardial salvage through reperfusion therapy. The study found that preconditioning did not significantly alter collateral blood flow, and the protective effect was independent of the major baseline predictors of infarct size, including area at risk and collateral blood flow. In the 3-hour study, preconditioning failed to limit infarct size, indicating that the protective effect of preconditioning is limited to shorter ischemic episodes. The study highlights the potential clinical relevance of preconditioning in delaying cell death and improving outcomes after myocardial infarction.Preconditioning with ischemia delays lethal cell injury in ischemic myocardium. This study investigated whether multiple brief ischemic episodes could protect the heart from a subsequent sustained ischemic insult. Two experiments were conducted: one with 40-minute occlusions and another with 3-hour occlusions. In the 40-minute study, preconditioning with four 5-minute ischemic episodes reduced infarct size to 25% of that in control animals (p < 0.001). In the 3-hour study, infarct sizes were similar between preconditioned and control groups. The protective effect in the 40-minute study may have been due to reduced ATP depletion and/or catabolite accumulation during sustained ischemia. These results suggest that multiple brief ischemic episodes, often preceding myocardial infarction in humans, may delay cell death after coronary occlusion, allowing greater myocardial salvage through reperfusion therapy. The study found that preconditioning did not significantly alter collateral blood flow, and the protective effect was independent of the major baseline predictors of infarct size, including area at risk and collateral blood flow. In the 3-hour study, preconditioning failed to limit infarct size, indicating that the protective effect of preconditioning is limited to shorter ischemic episodes. The study highlights the potential clinical relevance of preconditioning in delaying cell death and improving outcomes after myocardial infarction.