Objective: Ischemia-reperfusion causes lung damage to patients with congenital heart disease who undergo open surgery under total cardiopulmonary bypass. The aim of the present study was to compare ischemia-reperfusion-induced lung damage between adults and infants. Methods: Both infant (15 to 21-day-old) and adult (5 to 6-month-old) rabbits were subjected to either ischemia-reperfusion or sham operation. Ischemia-reperfusion was induced by clamping the right pulmonary hilum for 1 hour and then removing the clamp for 4 hours. The lung tissue samples were collected for histologic examination by light and electron microcopies and for biological evaluation of mitochondrial alterations. Blood samples were taken for measurement of interleukin-1β and tumor necrosis factor-α. Differences among the groups were analyzed by 2-way analysis of variance. Results: In comparison with adult lungs, the infant lungs had increased neutrophil infiltration, edema, swollen alveolar epithelial and endothelial cells, and severe mitochondrial impairment reflected by reduced swelling rate and membrane potential, intramitochondrial free Ca2+ levels after ischemia-reperfusion. The infant lungs produced higher levels of hydroxyl radical and malondialdehyde and lower levels of superoxide dismutase and glutathione peroxidase than adult lungs, especially after ischemia-reperfusion. The circulating levels of interleukin-1β and tumor necrosis factor-α were elevated during ischemia-reperfusion, particularly in the infants, which appeared to be associated with the expression of myeloid differentiation factor-88 and nuclear factor-κB in the lungs. Conclusion: Lung ischemia-reperfusion causes more severe lung damage in infants than in adults, probably because of the combination of low antioxidant capacity and overproduction of reactive oxygen species in infants. © 2008 The American Association for Thoracic Surgery.