The present study aimed to examine the effectiveness of bi-level positive airway pressure (BiPAP) versus continuous positive airway pressure (CPAP) in preterm infants with birth weight less than 1500 g and respiratory distress syndrome (RDS) following intubation-surfactant-extubation (INSURE) treatment. A two-center randomized control trial was performed. The primary outcome was the reintubation rate of infants within 72 h of age after INSURE. Secondary outcomes included bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP) and incidences of adverse events. Lung function at one year of corrected age was also compared between the two groups. There were 140 cases in the CPAP group and 144 in the BiPAP group. After INSURE, the reintubation rates of infants within 72 h of age were 15% and 11.1% in the CPAP group and the BiPAP group, respectively (P>0.05). Neonates in the BiPAP group was on positive airway pressure (PAP) therapy three days less than in the CPAP group (12.6 d and 15.3 d, respectively, P<0.05), and on oxygen six days less than in the CPAP group (20.6 d and 26.9 d, respectively, P<0.05). Other outcomes such as BPD, NEC, ROP and feeding intolerance were not significantly different between the two groups (P>0.05). There was no difference in lung function at one year of age between the two groups (P>0.05). In conclusion, after INSURE, the reintubation rate of infants within 72 h of age was comparable between the BiPAP group and the CPAP group. BiPAP was superior to CPAP in terms of shorter durations (days) on PAP support and oxygen supplementation. There were no differences in the incidences of BPD and ROP, and lung function at one year of age between the two ventilation methods.