Myocardial ischemia-reperfusion injury is at least partially mediated by oxygen-derived free radicals. Catalase is a major enzyme involved in the detoxification of hydrogen peroxide. The activity of catalase in the heart is very low, which may be a factor responsible for the high sensitivity of the heart to ischemia-reperfusion injury. The present study was undertaken to determine whether elevation of catalase specifically in the heart of transgenic mice can provide protection against ischemia-reperfusion injury. Hearts isolated from transgenic mice in which catalase in the heart was elevated approximately 60-fold higher than that in nontransgenic heart and from the non-transgenic littermates were subjected to 50 min of warm (37 degrees C) zero-flow ischemia followed by 90 min reflow. Compared with nontransgenic controls, transgenic hearts showed significantly improved recovery of contractile force (75 vs. 25% at the end of 90 min reperfusion, P < 0.01). Efflux of creatine kinase was reduced by approximately 50%, and the zone of myocardial infarction as demarcated by triphenyltetrazolium at the end of reperfusion was reduced by approximately 40% in transgenic hearts compared with nontransgenic controls. These findings support the view that hydrogen peroxide is an important cause of ischemia-reperfusion damage and suggest that protection may be provided by elevation of catalase activity.