Objective To determine whether early hyperoxemia in neonates with severe perinatal acidemia is associated with the development of hypoxic-ischemic encephalopathy (HIE). Study design We identified 120 infants at ≥36 weeks gestational age with perinatal acidosis born at Parkland Hospital who qualified for a screening neurologic exam for cooling therapy. Based on a PaO2 measurement during the first hour of life, the cohort was divided into infants with hyperoxemia (PaO2 >100 mmHg) and those without hyperoxemia (PaO2 ≤100 mmHg). The rate of moderate-severe encephalopathy was compared between the groups using χ2 analysis, as well as multiple logistic regression, taking into account baseline characteristics and confounding variables. Results Thirty-six infants (30%) had an initial PaO2 >100 mmHg. Infants with and without hyperoxemia had similar baseline maternal and infant characteristics. Infants with hyperoxemia had a higher incidence of HIE than those without hyperoxemia (58% vs 27%; P = .003). Admission hyperoxemia was associated with a higher risk of HIE (OR, 4; 95% CI, 1.4-10.5; adjusted P = .01). Among the neonates with moderate-severe HIE during the first 6 hours of life, those with hyperoxemia had a higher incidence of abnormal brain magnetic resonance imaging results, consistent with hypoxic ischemic injury, compared with those without hyperoxemia (79% vs 33%; P = .015). Conclusion In neonates with perinatal acidemia, admission hyperoxemia is associated with a higher incidence of HIE. Among neonates with HIE, admission hyperoxemia is associated with abnormal brain magnetic resonance imaging findings. The judicious use of oxygen during and after resuscitation is warranted.