Abstract: Objective To explore the efficacy of duo positive airway pressure ventilation in treating preterm infant with neonatal respiratory distress syndrome (RDS). Methods 65 preterm infants admitted to the neonatal intensive care unit from December 2012 to December 2013 were randomly divided into DuoPAP group (34 cases) or NCPAP (31 cases) group. Blood gas analysis(pH value, PaO2, PaCO2 and OI) at 1h, 12h, 24h, and 72h, and incidence of apnea, pulmonary air leak, repeated application of pulmonary surfactant and non-invasive ventilation failure at 72h in the two groups were measured and compared after using intubate surfactant extubate (INSURE). Results OI after non-invasive ventilation at 1h, 12h, and 24h was significantly higherin DuoPAP group than that in NCPAP group P<0.01). PaCO2 after non-invasive ventilation at 1h, 12h, 24hand 72h was significantly lower in DuoPAP group than that in NCPAP group (P<0.01). PaO2 after non-invasive ventilation at 1h and 12h was higher in DuoPAP group than that in NCPAP group, and there was significant difference between the two groups (P<0.01). The incidence of non-invasive ventilation failure, apnea in 72h was lower in DuoPAP group than that in NCPAP group, and there was significant difference between the two groups (P<0.05). Conclusions Compared with NCPAP, DuoPAP is more feasible for improving oxygenation, decreasing the need for mechanical ventilation in 72h in preterm infants with neonatal RDS.