The optimal oxygen concentration for the resuscitation of term infants remains controversial. We studied the effects of 21 versus 100% oxygen immediately after birth, and also exposure for 24 h to 100% oxygen, on oxidant lung injury and lung antioxidant enzyme (AOE) activities in term newborn lambs. Lambs at 139 d gestation were delivered and ventilated with 21% (RAR) or 100% (OXR) for 30 min. A third group of newborn lambs were ventilated with 100% O2 for 24 h (OX24). Oxidized glutathione levels in whole blood were significantly different among the groups with lower values in the RAR group, and these values correlated highly with partial pressure of arterial oxygen (Pao2). The reduced to oxidized glutathione ratio was significantly different among the groups, the ratio decreasing with increasing oxygen exposure. Lipid hydroperoxide (LPO) activity was significantly higher in the OXR and OX24 groups. AOE activity was higher in the whole lung and in red cell lysate in the OX24 group. Increased myeloperoxidase (MPO) activity, percent neutrophils, and proteins in lung lavage suggested inflammation in the OX24 group after maximal oxygen exposure. We conclude that even relatively brief exposure of the lung to 100% oxygen increases systemic oxidative stress and lung oxidant injury in ventilated term newborn lambs.