Lazaroid U-74500A, a 21-aminosteroid that inhibits iron-dependent lipid peroxidation, was previously shown to have protective effects on neuronal viability in animal models of ischemic neurologic injury. To test the hypothesis that lazaroid enhances myocardial salvage after ischemia/reperfusion, lazaroid-pretreated rats (2 mg/ kg intravenously) (n = 26) and control rats pretreated with vehicle (n = 22) were subjected to 45-min left coronary (LCA) occlusion followed by 120 min of reflow. Lazaroid-pretreated rats and controls had similar ischemic risk areas (AR), as determined by phthalocyanine blue dye staining (47.2 ± 2.3 vs. 48.2 ± 3.0%, p = NS, mean ± SEM). Infarct size, measured by triphenyltetra-zolium staining, was markedly reduced in lazaroid-treated rats as compared with controls (6.0 ± 1.5 vs. 22.2 ± 3.9%, p = 0.001, infarct size/ischemic RA × 100). There were no differences in systolic blood pressure (SBP), heart rate (HR), rate-pressure product (RPP), or maximum rate of left ventricular systolic pressure development (LVdP/dt) between groups during ischemia or reperfusion. Lazaroid pretreatment enhances myocardial salvage after 45-min LCA occlusion and 2-h reflow in this animal model. This beneficial effect is independent of the hemodynamic determinants of myocardial oxygen demand.