This study assesses the effect of ischemic preconditioning (IP) on the magnitude of ST segment shift. Anesthetized rabbits were subjected to IP (four periods of 5-min coronary artery occlusion followed by 5-min reperfusion; n = 9) or control (no IP; n = 9). Thereafter, both groups were subjected to 60 min of ischemia. There was a gradual decline in the magnitude of ST segment elevation, recorded by an epicardial lead overlying the ischemic zone. ST amplitude after 1 min of ischemia was 2.19 +/- 0.51, 1.29 +/- 0.44, 0.72 +/- 0.26, 0.20 +/- 0.10, and 0.26 +/- 0.13 mV, during the first, second, third, fourth IP episodes and the final ischemic period respectively (P = 0.0003). ST amplitude after 2 min of ischemia was 2.56 +/- 0.69, 2.47 +/- 0.55, 1.82 +/- 0.42, 1.13 +/- 0.23, and 1.02 +/- 0.14 mV, respectively (P = 0.0043). While heart rate and mean blood pressure at 1, 2, 30, and 60 min of the final long ischemia were similar in both groups, the IP group had less ST elevation (P = 0.0074). There was no change in RMBF between the first IP and the final occlusion. Both groups were equally ischemic during the long occlusion. In the rabbit, progressive reduction in ST segment shift with repeated ischemia is caused by preconditioning and is independent of the recruitment of collaterals or of hemodynamic changes.