Increased oxidative stress is associated with perinatal asphyxia and respiratory distress in the newborn period. Induction of nuclear factor erythroid 2 p45-related factor (Nrf2) has been shown to decrease oxidative stress through the regulation of specific gene pathways. We hypothesized that Nrf2 attenuates mortality and alveolar growth inhibition in newborn mice exposed to hyperoxia. Nrf2^+/+and Nrf2^-/- newborn mice were exposed to hyperoxia at 24 hours. Survival was significantly less in Nrf2^-/- mice exposed to 72 hours of hyperoxia and returned to room air (p<0.0001) and in Nrf2^-/- mice exposed to hyperoxia for eight continuous days (p<0.005). To determine the response of Nrf2 target genes to hyperoxia, glutathione peroxidase (Gpx2) and NAD(P)H:quinone oxidoreductase (NQO1) expression was measured from lung of newborn mice using real-time PCR. In the Nrf2^+/+ mice, significant induction of lung Gpx2 and NQO1 above room air controls was found with hyperoxia. In contrast, Nrf2^-/- mice had minimal induction of lung Gpx2 and NQO1 with hyperoxia. Expression of p21 and IL-6, genes not regulated by Nrf2, were also measured. IL-6 expression in Nrf2^-/- lung was markedly induced by 72 hours of hyperoxia in contrast to the Nrf2^+/+ mice. p21 was induced in both Nrf2^+/+ and Nrf2^-/-lung by hyperoxia. Mean linear intercept (MLI) and mean chord length (MCL) were significantly increased in 14 day old Nrf2^-/- mice previously exposed to hyperoxia compared to Nrf2^+/+mice. The percentage of Sp-c⁺ type 2 alveolar cells in 14 day-old Nrf2^-/- mice exposed to neonatal hyperoxia was also significantly less then Nrf2^+/+mice (p<0.02). In summary these findings indicate that Nrf2 increases survival in newborn mice exposed to hyperoxia and that Nrf2 may help attenuate alveolar growth inhibition caused by hyperoxia exposure.