Recently, mounting evidence has emerged to suggest that hyperbaric oxygenation (HBOT)-induced neuroprotection following experimental global ischemia and subarachnoid hemorrhage entails a decrease in the expression of hypoxia-inducible factor-1 (HIF-1). Therefore, the purpose of this study was to test the hypothesis that oxygen-induced neuroprotection following neonatal hypoxia-ischemia involves alterations in the expression of HIF-1. Seven-day-old rat pups were subjected to unilateral carotid artery ligation followed by 2hrs of hypoxia (8% O2 at 37°C). The administration of HBOT (2.5ATA) or normobaric oxygenation treatment (NBOT) for 2hrs. The expression and phosphorylation status of HIF-1 was evaluated at intervals up to 24hrs after the insult, as was the expression of glucose transporter (Glut)-1, Glut-3, LDH, ALD, and p53. The protein-protein interaction of HIF-1 and p53 was also examined. An elevated expression of HIF-1, Glut-1, Glut-3, ALD, and LDH was observed after the insult. An increase in the dephosphorylated form of HIF-1 was followed by an increase in the association of HIF-1 with p53 and an increase in p53 levels. Both, HBOT and NBOT reduced the elevated expression of HIF-1° and decreased its dephosphorylated form. Furthermore, both treatments promoted a transient increase in the expression of Glut-1, Glut-3, LDH, and ALD, while decreasing the HIF-1-p53 interaction and decreasing the expression of p53. Therefore, the alteration of the HIF-1 phenotype by a single oxygen treatment may be one of the underlying mechanisms for the observed oxygen-induced neuroprotection seen when oxygen is administered after a neonatal hypoxic-ischemic insult.