We assessed the myocardial susceptibility to ischemic-reperfusion injury in obese rat hearts in the absence and the presence of predicted circulating concentrations of insulin and fatty acids. Feeding rats a high calorie diet resulted in increases in body weight, visceral fat content, cardiac hypertrophy, and plasma insulin, non-esterified free fatty acid and triglyceride concentrations. In the absence of both insulin and fatty acids in the coronary perfusate, the hearts of obese rats developed an increased infarct size (41.9±1.9% for obese vs 22.9±2.3% for control, p<0.05) and a reduced percentage recovery of aortic output (4.2±4.2% for obese vs 27.7±3.4% for controls, p<0.05) after coronary artery occlusion and reperfusion. In the presence of insulin in the coronary perfusate, a cardioprotective effect was noted in both groups, an action that was greater in hearts from obese as compared to control rats and which abolished the obesity-induced changes in infarct size (13.8±1.2% for controls vs. 21.0±1.6% for obese), and percentage recovery of aortic output (60.2±4.7% for controls vs. 45.7±9.4% for obese). Fatty acids (0.7mM, control and 1.5mM, obese) added to the coronary perfusate with in vivo concentrations of insulin dramatically increased infarct size (48.2±3.1% for obese, 37.5±2.7% for control. p<0.05 vs without fatty acids) and decreased percentage aortic output recovery (control, 10.4±5.2%, obese 7.8±3.5%. p<0.05 vs without fatty acids) in both groups to similar values. In conclusion, in obesity the impact of an increased susceptibility of the myocardium to ischemic-reperfusion injury on myocardial injury is likely to be overshadowed by the comparatively greater roles played by predicted increases in circulating insulin and fatty acids found in vivo. These data support the notion that adiposity per se is unlikely to be a valuable predictor of outcomes in ischemic-reperfusion injury.