Compared to the lean Lou/C rat, the Wistar rat develops increased body weight and abdominal adiposity (IAA). The aim of this study was to compare the functional response to cardiac ischemia/reperfusion of 3-month old Wistar rats with age-matched Lou/C rats, and to explain the differences with regards to mitochondrial hydrogen-peroxide release (mH 2 O 2 r). Langendorff-perfused hearts of Lou/C and Wistar rats were subjected to ischemia (25 min) followed by reperfusion (30 min). Cardiac function was monitored throughout the experiment. Mitochondria were extracted before and after ischemia, and their oxidative capacities, mH 2 O 2 r, and activity of the respiratory-chain complex were measured. The IAA of Wistar rats was associated with slight glucose intolerance and noticeable functional abnormalities of the myocardium during post-ischemic reperfusion. Cardio-toxicity was related to maintenance of the activity of respiratory-chain complex II and increased mH 2 O 2 r, whereas cardio-protection in lean Lou/C rats occurred through reduced complex-II activity and mH 2 O 2 r. In conclusion, IAA and/or systemic glucose intolerance maintained complex-II activity during post-ischemic reperfusion, thus increasing mH 2 O 2 r through reverse electron flux and inducing significantly increased cardio-toxicity. Inhibitors of respiratory complex II could thus help protect the heart against ischemia/reperfusion in obese individuals.