Summary The effects of the nonsteroidal antiinflammatory agent, ibuprofen, were evaluated in two animal models of myocardial ischemia: regional myocardial ischemia produced by temporary occlusion followed by reperfusion of the canine left circumflex coronary artery (LCX), and global ischemia in the isolated, blood-perfused feline heart. In control dogs (n = 12), 60 min of LCX occlusion followed by 24 h of reperfusion resulted in 51 ± 4% of the area at risk, and 20 ± 2% of the total left ventricle becoming infarcted. The average infarct size of the group of dogs receiving oral ibuprofen (n = 12: dose of 12.5 mg/kg, q4h) was 33 ± 5% of the area at risk, and 12 ± 2% of the total left ventricle, a reduction in infarct size as compared to the controls of 35% (p > 0.02) and 39% (p < 0.02), respectively. The mechanism by which ibuprofen provided these beneficial effects could not be attributed to a reduction in myocardial oxygen consumption (MO2), estimated by rate–pressure products, or redistribution of regional myocardial blood flow, assessed by radioactive microspheres. The direct effect of ibuprofen on ischemic myocardium was assessed in an isolated, blood-perfused cat heart model of global ischemia. After 60 min of normothermic global ischemia, left ventricular pulse pressure of control hearts (n = 8) at 5 and 10 mm Hg end-diastolic pressure was reduced by 56 ± 97% and 60 ± 12%, respectively, relative to preischemic values. Administration of ibuprofen (12.5 mg/kg, i.v., to the blood donor cat, n = 6) did not significantly prevent the ischemia-induced deterioration of left ventricular function. Normothermic ischemia for 60 min resulted in a significant reduction in MO2 in both the control and ibuprofen-treated hearts. However, after 1 h of reperfusion, the average MO2 for the ibuprofen-treated hearts was 96% greater (4.5 ± 0.4 versus 2.3 ± 0.5 ml/min/100 g) than the average MO2 of the control hearts. While conventional thinking contends that myocardial infarct size may be limited by a reduction in MO2 or a redistribution of blood flow, the data from this study indicate that these two mechanisms are not relevant in the case of ibuprofen.