Face-mask ventilation is the most common resuscitation method for birth asphyxia. Ventilation with a cuffless laryngeal mask airway (LMA) has potential advantages over face-mask ventilation during neonatal resuscitation in low-income countries, but whether the use of an LMA reduces mortality and morbidity among neonates with asphyxia is unknown. In this phase 3, open-label, superiority trial in Uganda, we randomly assigned neonates who required positive-pressure ventilation to be treated by a midwife with an LMA or with face-mask ventilation. All the neonates had an estimated gestational age of at least 34 weeks, an estimated birth weight of at least 2000 g, or both. The primary outcome was a composite of death within 7 days or admission to the neonatal intensive care unit (NICU) with moderate-to-severe hypoxic-ischemic encephalopathy at day 1 to 5 during hospitalization. Complete follow-up data were available for 99.2% of the neonates. A primary outcome event occurred in 154 of 563 neonates (27.4%) in the LMA group and 144 of 591 (24.4%) in the face-mask group (adjusted relative risk, 1.16; 95% confidence interval CI, 0.90 to 1.51; P = 0.26). Death within 7 days occurred in 21.7% of the neonates in the LMA group and 18.4% of those in the face-mask group (adjusted relative risk, 1.21; 95% CI, 0.90 to 1.63), and admission to the NICU with moderate-to-severe hypoxic-ischemic encephalopathy at day 1 to 5 during hospitalization occurred in 11.2% and 10.1%, respectively (adjusted relative risk, 1.27; 95% CI, 0.84 to 1.93). Findings were materially unchanged in a sensitivity analysis in which neonates with missing data were counted as having had a primary outcome event in the LMA group and as not having had such an event in the face-mask group. The frequency of predefined intervention-related adverse events was similar in the two groups. In neonates with asphyxia, the LMA was safe in the hands of midwives but was not superior to face-mask ventilation with respect to early neonatal death and moderate-to-severe hypoxic-ischemic encephalopathy. (Funded by the Research Council of Norway and the Center for Intervention Science in Maternal and Child Health; NeoSupra ClinicalTrials.gov number, NCT03133572.).