The enthusiastic clinical reports on normothermic blood cardioplegia contrast with the paucity of data on the myocirdial metabolic effects of this technique. The present study was therefore designed to assess whether normothermic blood cardioplegia really provides an aerobic environment during aortic cross-clamping. Thirty-one patients undergoing coronary (16 patients), valve (13 patients), and transplantation (2 patients) procedures were given continuous normothermic blood cardioplegia through the coronary sinus. Myocardial metabolism was assessed either immediately before aortic unclamping (16 patients) by collecting blood simultaneously from the cardioplegia infusion line and the aortic effluent or during reperfusion (15 patients) by collecting blood simultaneously from the radial artery and the coronary sinus. All samples were assayed for markers of anaerobiosis (blood gases, lactates), leukocyte activation (elastase), and lipid peroxidation (malondialdehyde, vitamin E). At the end of arrest, oxygen extraction was low, whereas the production of lactates was small, thereby suggesting the efficacy of normothermic blood cardioplegia in maintaining a predominantly aerobic metabolism. This was confirmed by postarrest data, as oxygen extraction measured immediately after cross-clamp removal was unchanged from prearrest values, whereas lactate metabolism yielded transient and limited production followed by prompt recovery of normal extraction patterns. There was no release of elastase from the myocardium, which suggests adequate protection of the coronary endothelium from ischemic injury and the related increase in leukocyte activation. Likewise, postarrest coronary sinus concentrations of malondialdehyde and vitamin E were identical to the respective arterial concentrations, thereby ruling out the occurrence of intramyocardial lipid peroxidation at the time of reperfusion. This absence of oxidative reperfusion injury further supports the idea that no (or minimal) ischemic injury occurred during the preceding cross-clamp period. We conclude that normothermic blood cardioplegia can effectively keep the heart in a predominantly aerobic state during aortic cross-clamping, which makes its use particularly attractive in patients who have limited tolerance to intraoperative myocardial ischemia. © 1992.