Myocardial ischemia causes release of chemotactic factors, migration of neutrophils, peroxidation of lipids, and depletion of free radical scavengers. The invading neutrophils may injure the myocardial vasculature and sarcolemma by generating oxygen free radicals. Several agents that affect neutrophils or oxygen radicals were evaluated in a canine model of regional myocardial ischemia and reperfusion. Anesthetized dogs underwent occlusion and reperfusion of the left circumflex coronary artery. Infarct zone, area at risk of infarction, and total left ventricle were quantified by gravimetric and planimetric analysis. Limitation of infarct size by ibuprofen was associated with marked suppression of leukocyte accumulation within the ischemic myocardium. Neutrophil depletion by antiserum resulted in similar reductions of infarct size and was accompanied by a reduction in leukocyte infiltration. A combination of oxygen radical scavengers, superoxide dismutase plus catalase, decreased myocardial injury whether infusion began before occlusion or 75 min after occlusion. None of the treatments significantly altered hemodynamic indices of myocardial oxygen demand. Reduction of infarct size by ibuprofen, neutrophil antiserum, and free radical scavengers indicates that neutrophils and oxygen radicals participate in producing the irreversible damage to the myocardium during ischemia and reperfusion.