It is unknown whether ischemic preconditioning (PC; either early or late) occurs in the mouse. The goal of this study was to answer this question and to develop a reliable and physiologically relevant murine model of both early and late ischemic PC. A total of 201 mice were used. In nonpreconditioned open-chest animals subjected to 30 min of coronary occlusion followed by 24 h of reperfusion, infarct size (tetrazolium staining) averaged 52% of the region at risk. When the 30-min occlusion was performed 10 min after a PC protocol consisting of six cycles of 4-min occlusion and 4-min reperfusion, infarct size was reduced by 75%, indicating an early PC effect. When the 30-min occlusion was performed 24 h after the same PC protocol, infarct size was reduced by 48%, indicating a late PC effect. In mice in which the 30-min occlusion was followed by 4 h of reperfusion, infarct size was similar to that observed after 24 h of reperfusion, indicating that a 4-h reperfusion interval is sufficient to detect the final extent of cell death in this model. Fundamental physiological variables (body temperature, arterial oxygenation, acid-base balance, heart rate, and arterial pressure) were measured and found to be within normal limits. Taken together, these results demonstrate that, in the mouse, a robust infarct-sparing effect occurs during both the early and the late phases of ischemic PC, although the early phase is more powerful. This murine model is physiologically relevant, provides reliable measurements, and should be useful for elucidating the cellular mechanisms of ischemic PC in genetically engineered animals.