Early growth response gene-1 (Egr-1) is up-regulated by hypoxia-ischemia (HI) and reactive oxygen species (ROS) in adult animals, functioning as a master switch in inflammation and thrombogenesis. We hypothesized that resuscitation from HI with 100% O2 would result in greater Egr-1 expression, ROS, and cell death (CD) in the brains of newborn piglets than 21% O2. Two control groups breathed 21% O2 for 1 h followed by 21% or 100% O2 for 1 h. Two HI groups underwent carotid artery occlusion and breathed 8-12% O2 for 1 h followed by occlusion release and 21% or 100% O2 for 1 h. Brain Egr-1 mRNA and protein were analyzed via quantitative PCR and Western blot. CD and ROS were measured by fluorescence microscopy. Egr-1 mRNA expression increased throughout the brain in response to HI with regional heterogeneity, but protein levels did not. Resuscitation with 100% oxygen did not cause any additional Egr-1 mRNA, Egr-1 protein, CD, or ROS production as compared with 21% oxygen. There was no difference in physiologic recovery after HI with room air compared with 100% O2 resuscitation. However, 100% O2 administration was associated with increased CD in the brainstem independent of HI. Therefore, 100% O2 may have been toxic to some brainstem cells and potentially have significance in long-term neurologic sequelae seen after neonatal HI/resuscitation. Egr-1 protein levels may be tightly regulated in an attempt to diminish neurotoxicity or to enhance plasticity at this stage of development.