High oxygen concentrations reduced infarct size in prereperfusion era studies; however, with reperfusion therapy, high oxygen tension carries the theoretical risk of exacerbating reperfusion injury by increasing toxic oxygen-derived free radicals. In this study, two groups of dogs underwent 90 minutes of coronary occlusion and 72 hours of reperfusion. The oxygen group (n = 16) received 100% inspired oxygen from 20 minutes before reperfusion through 3 hours of reperfusion, whereas the room-air group (n = 19) was ventilated with room air. Infarct size (as a percentage of risk area) was reduced by 38% in the oxygen group (26.7% +/- 4.7% vs 43.3% +/- 4.3%; p = 0.017). This benefit was independent of underlying variability in collateral blood flow in individual dogs (p = 0.016 by analysis of covariance [ANCOVA]). Left ventricular ejection fraction was significantly improved in the oxygen group (43% +/- 3% vs 33% +/- 2%; p = 0.008), as was regional function in the infarct zone (p < 0.05). These data suggest that high concentrations of inspired oxygen may also benefit patients with acute myocardial infarction who undergo reperfusion therapy.