Twenty-one immature piglets (< 3 weeks old) underwent 30 minutes of aortic clamping with hypocalcemic glutamate/aspartate blood cardioplegia. Six piglets underwent hyperoxemic cardiopulmonary bypass and blood cardioplegia without preceding hypoxemia (control). Fifteen piglets became hypoxemic (oxygen tension about 25 mm Hg) for up to 2 hours by decreasing ventilator fraction of inspired oxygen to 6% to 7% before cardiopulmonary bypass. Of these, six piglets underwent 5 minutes of abrupt hyperoxemic uncontrolled reoxygenation by starting cardiopulmonary bypass at oxygen tension of about 400 mm Hg before they received oxygen tension of about 400 mm Hg blood cardioplegia. Nine others underwent controlled cardiac reoxygenation by starting cardiopulmonary bypass at ambient oxygen tension (about 25 mm Hg) followed 5 minutes later by 30 minutes of cardiopulmonary bypass at normoxemic oxygen tension (about 100 mm Hg) before raising oxygen tension to about 400 mm Hg. Myocardial function after cardiopulmonary bypass was evaluated from end-systolic elastance by conductance catheter, oxidant damage was estimated by measuring transcoronary conjugated diene levels to detect lipid peroxidation, and antioxidant reserve capacity was determined by measuring malondialdehyde produced from myocardium incubated with the oxidant t-butylhydroperoxide. Hyperoxemic cardiopulmonary bypass and blood cardioplegia preserved myocardial function and produced no oxidant damage in nonhypoxemic piglets. In contrast, uncontrolled reoxygenation at oxygen tension about 400 mm Hg, followed by blood cardioplegia, resulted in marked conjugated dienes production (42 +/- 4* vs 3 +/- 1) A233 nm/min/100 g during blood cardioplegic induction, reduced antioxidant reserve capacity malondialdehyde at 4 mmol/L t-butylhydroperoxide; 1342 +/- 59* vs 958 +/- 50 nmol/g protein) and caused profound myocardial dysfunction; end-systolic elastance recovered only 21% +/- 2%* despite a blood cardioplegic regimen that was cardioprotective in nonhypoxemic piglets. Conversely, controlled cardiac reoxygenation reduced lipid peroxidation (conjugated dienes production was 2 +/- 1**), restored antioxidant reserve capacity (malondialdehyde at 4 mmol/L t-butylhydroperoxide; 982 +/- 88**), and allowed near-complete (83 +/- 8%**) functional recovery. We conclude that reoxygenation of the hypoxemic immature heart by initiating conventional hyperoxemic cardiopulmonary bypass causes oxidant damage characterized by lipid peroxidation, reduced antioxidant reserve capacity, and results in functional depression that nullifies the cardioprotective effects of blood cardioplegia. These changes can be reduced by starting cardiopulmonary bypass at the ambient oxygen tension of the hypoxemic subject and delaying subsequent reoxygenation until blood cardioplegic induction by controlled cardiac reoxygenation (*p < 0.05 vs control; **p < 0.05 vs uncontrol reoxygenation) and analysis of variance.