Continuous positive airway pressure (CPAP) delivered via binasal prongs has been the cornerstone of respiratory management in preterm infants. Though effective, the use of binasal prongs is associated with nasal trauma, and CPAP failure. To overcome these issues, nasal masks are increasingly used to deliver CPAP in preterm infants. The aim was to conduct a systematic review of randomized controlled trials (RCTs) comparing nasal mask versus binasal prongs to deliver CPAP in preterm infants. Medline, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index of Nursing, and Allied Health Literature, and E-abstracts from the Pediatric Academic Society meetings were searched in May 2017. All RCTs comparing nasal mask versus binasal prongs for delivering CPAP in preterm infants were included. Primary outcome was CPAP failure (need for mechanical ventilation within 72 h of initiating CPAP). Secondary outcomes included duration of CPAP, moderate to severe nasal trauma, any nasal trauma, pneumothorax, severe IVH, bronchopulmonary dysplasia at 36 weeks postmenstrual age, and mortality. Five RCTs with low risk of bias were included. Nasal mask significantly decreased the risk of CPAP failure (4 RCTs [N = 459]; relative risk [RR]: 0.63; 95% confidence interval [CI]: 0.45-0.88; P=.007; I2 = 0%, NNT: 9), and the incidence of moderate to severe nasal trauma (3 RCTs [N = 275], RR: 0.41; 95%CI, 0.24-0.72; P = 0.002; I2 = 74%, NNT: 6). Other outcomes did not differ significantly between the groups. Compared to binasal prongs, nasal mask may provide a safe and effective alternative by minimizing the risk of CPAP failure in preterm infants needing CPAP support.