Cardiopulmonary bypass is associated with a reduction in plasma free triiodothyronine in patients undergoing cardiac operations. A previous experimental study in pigs demonstrated a marked inotropic effect when triiodothyronine was administered after a period of myocardial ischemia and cardiopulmonary bypass; this was associated with a significant reduction in mortality compared with the mortality in control pigs. To clarify the effect of triiodothyronine on myocardial high energy phosphate stores and lactate, a series of experiments was done in baboons undergoing 3 hours of myocardial ischemia while supported by cardiopulmonary bypass. Seven baboons received no triiodothyronine and six received 6 μg of triiodothyronine at the end of the ischemic period. Seventy minutes after cardiopulmonary bypass, the myocardial adenosine triphosphate level was significantly higher (p < 0.01) in the treated animals. In untreated animals, a steady increase in myocardial lactate occurred after cardiopulmonary bypass; by 120 minutes after ischemia (70 minutes after cardiopulonary bypass) there was a significant difference in lactate levels between the two groups (p < 0.01). We postulate that a combination of global ischemia and depletion of triiodothyronine results in reduced mitochondrial function, inhibition of the tricarboxylic acid cycle, and increased anaerobic metabolism and depletion of myocardial phosphates. Triiodothyronine replacement therapy leads to improved mitochondrial function and increased aerobic metabolism, which results in increased synthesis of myocardial phosphates. We suggest that there may be a place for the administration of triiodothyronine in patients undergoing cardiac operations with a prolonged myocardial ischemic period or in whom there is any evidence of low cardiac output after discontinuation of cardiopulmonary bypass.