Cyanotic hearts are associated with depleted endogenous antioxidants (glutathione peroxidase, superoxide dismutase, and catalase), and thereby is more susceptible to myocardial ischemia/reperfusion injury during open heart surgery compared with acyanotic ones. Clinically, when surgery is performed on cyanotic infants, cardiopulmonary bypass (CPB) is usually initiated at high PaO(2), without consideration of possible cytotoxic effects of hyperoxia. The concept of "surgical reoxygenation injury of cyanotic myocardium" was proposed, wherein unintended abrupt reoxygenation of cyanotic myocardium at the onset of routine CPB causes oxygen-mediated injury, which may render the reoxygenated myocardium more susceptible to subsequent surgical ischemia/reperfusion injury and accentuates post-CPB myocardial dysfunction. The experimental studies using acute and chronic hypoxia models confirmed the role of reoxygenation injury mediated by reactive oxygen species in the pathogenesis of post-CPB myocardial dysfunction and addressed the importance of controlling PaO(2) at the onset of CPB. The clinical relevance of this injury was shown by subsequent clinical studies, which demonstrated depleted antioxidant reserve capacity and troponin release during the initial reoxygenation on hyperoxic CPB prior to cardioplegic arrest. Furthermore recent randomized clinical trials verified that hyperoxic CPB provokes biochemical multi-organ damage including myocardium, lung, liver, and brain after open heart surgery in cyanotic patients, which can be successfully reduce by normoxic CPB management (i.e., reducing PaO(2) at onset of CPB, gradual reoxygenation and controlled reoxygenation protocol). Based on these experimental and clinical studies, avoidance of using hyperoxic PaO(2) on routine CPB is strongly recommended in the cyanotic patients.