Abstract More than 80% of the 3 million women who labor and deliver each year in the United States undergo continuous electronic fetal monitoring (EFM) during labor. The goal of such monitoring is to identify fetal hypoxia and prevent the transition to acidemia, expedited operative delivery, and/or neonatal morbidity. Category II EFM, the most commonly observed group of fetal heart rate features, is associated with variable risks for acidemia. One common response to Category II EFM is maternal oxygen (O2) supplementation. The theoretic rationale for O2 administration is that it increases O2 transfer to a hypoxic fetus, thereby reversing hypoxia and preventing acidemia. This practice is so commonly used that 2 out of 3 patients receive supplemental O2 at some point during labor. However, despite the theoretic rationale, there is no rigorous data to support its widespread use. Our pilot randomized noninferiority trial, published in JAMA Pediatrics, demonstrated that room air was noninferior to O2 for improving umbilical artery lactate, a surrogate marker of fetal acidemia and neonatal morbidity. Our subsequent meta-analysis of randomized trials investigating O2 versus room air at time of cesarean section or vaginal delivery found no differences in umbilical artery pH, rates of acidemia, and neonatal intensive care unit admissions between room air and O2 groups. Importantly, none of the trials studied important clinical measures of neonatal or maternal morbidity and only one trial studied O2 in the setting of Category II EFM. The current state of evidence is limited in several ways. First, the existing studies of O2 in labor vary in the dose, duration, and timing of O2 administration. Second, only one pilot trial investigated the utility of O2 supplementation for the ACOG-recommended indication of Category II EFM. Third, all of the studies have used surrogate measures of neonatal morbidity such as cord gases or neonatal intensive care unit admission. Finally, none of the studies were powered to assess the impact of O2 administration on neonatal clinical sequelae of in utero hypoxia or operative delivery. Without data on these definitive outcomes, evidence-based recommendations for managing Category II EFM cannot be made. To fill this important knowledge gap, we propose a large, multicenter, randomized noninferiority trial of O2 supplementation versus room air in patients with Category II EFM in labor. Our central hypothesis is that clinically relevant maternal and neonatal outcomes will not significantly differ between the two arms. We will pursue the following specific aims: 1) Determine the effect of room air, compared with supplemental O2, on neonatal morbidity among patients with Category II EFM and 2) Determine the effect of room air, compared with supplemental O2, on rates of operative delivery. A total of 2124 patients will be randomized to provide adequate power to detect clinically meaningful noninferiority margins for the above stated outc...