Abstract: Objective To compare the clinical effectiveness of nasal intermittent positive pressure ventilation (NIPPV) and nasal continuous positive airway pressure (NCPAP) in the treatment of respiratory distress syndrome (RDS) in premature infants. Methods A total of 142 premature infants with a gestational week of 28 weeks to 32⁺⁶ weeks and < 2 500 g of birth weight were enrolled and their clinical data were retrospectively analyzed. They were divided into an NCPAP group (n=75) and an NIPPV group (n=67) according to the preferred non-invasive ventilation mode at admission. Both groups were compared for non-invasive respiratory effectiveness and adverse reactions. Results The NIPPV group presented remarkable decreases in endotracheal intubation rate and pulmonary infection incidence (P<0.05), as well as significant increases in feeding intolerance (P<0.05), compared with the NCPAP group. There were no statistical differences in total parenteral feeding time, the use of pulmonary surfactant (PS), and the length of hospitalization stay and hospitalization expenses (P> 0.05). There was no statistically significant differences between the NIPPV group and the NCPAP group in the incidence of mortality, bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), patent ductus arteriosus (PDA), nose mucosal injury, and lung leakage (P>0.05). Conclusions Compared with NCPAP, NIPPV can reduce the utilization rate of mechanical ventilation, without increasing the incidence of nasal mucosal damage and serious feeding problems. Therefore, NIPPV can be used as the first-choice non-invasive ventilation mode in the treatment of the premature.