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To test the hypothesis that intrauterine hyperoxemia is associated with an increased risk of neonatal morbidity.This was a secondary analysis of a prospective study of singleton, nonanomalous deliveries at or beyond 37 weeks of gestation at an institution with a universal umbilical cord gas policy from 2010 to 2014. The primary outcome was a composite of neonatal morbidity including neonatal death, meconium aspiration syndrome, intubation, mechanical ventilation, hypoxic–ischemic encephalopathy, and hypothermic therapy. Intrauterine hyperoxemia was defined as umbilical vein partial pressure of oxygen 90th percentile or greater of the cohort. Adjusted relative risks (RRs) were estimated for neonatal morbidity controlling for confounders. Analysis was performed for the entire cohort and stratified by the presence of acidemia defined as umbilical artery pH less than 7.1.Of 7,789 patients with validated paired cord gases, 106 (1.4%) had the composite neonatal morbidity. There was no difference in composite neonatal morbidity in patients with and without intrauterine hyperoxemia in the entire cohort (1.5% compared with 1.3%, adjusted RR 1.5, 95% confidence interval [CI] 0.9–2.7). The rate of acidemia was not significantly different in the two groups (1.9% compared with 1.8%, adjusted RR 1.5, 95% CI 0.9–2.5). In stratified analysis, there was evidence of effect modification (P for interaction <.001) with a significant association between intrauterine hyperoxemia and neonatal morbidity in the presence of acidemia (41.2% compared with 21.4%, adjusted RR 2.3, 95% CI 1.1–3.5), but not in its absence (0.8% compared with 1.0%, adjusted RR 1.0, 95% CI 0.5–2.2).Intrauterine hyperoxemia, compared with normoxemia, is associated with a small but significantly increased risk of neonatal morbidity in acidemic neonates.