The present study was designed and conducted to compare the efficacy between nasal continuous positive airway pressure (NCPAP), nasal intermittent positive-pressure ventilation (NIPPV), and noninvasive high-frequency oscillatory ventilation (NHFOV) as the primary noninvasive ventilation in preterm infants with respiratory distress syndrome (RDS). This multicenter retrospective cohort study was performed using data from four tertiary neonatal intensive care units (NICUs) in China between 2016 and 2018. 512 preterm infants with RDS who received early non-invasive ventilation (NIV) were analyzed. Propensity score analysis with 1 : 1 matching was performed with the nearest neighbor matching method using calipers of width equal to 0.1 of the standard deviation of the logit of the propensity score. The primary outcome was the need for intubation and invasive mechanical ventilation (IMV) within the first 7 days after birth. Secondary outcomes were days of hospitalization, predischarge mortality, rate of retinopathy of prematurity (ROP) > stage II, rate of bronchopulmonary dysplasia (BPD) at 36 weeks post-menstrual age, rate of air leaks, rate of intraventricular hemorrhage (IVH) ≥ grade 3, and rate of necrotizing enterocolitis (NEC) ≥ stage II. Propensity score matching identified 126 infants in each cohort (NHFOV vs. NIPPV), 96 infants in each cohort (NHFOV vs. NCPAP), 134 infants in each cohort (NIPPV vs. NCPAP) respectively. The need for IMV was significantly lower in the NHFOV as compared with NCPAP and NIPPV groups respectively (13/126 vs. 27/126, p = 0.016; 9/96 vs. 20/96, p = 0.027), while no difference was observed between NIPPV and NCPAP groups (25/134 vs. 25/134, p = 0.805). However, the number of days of hospitalization in NIPPV was significantly lower than that of the NCPAP group (24.8 ±14.6 days vs. 33.2 ±20.2 days p = 0.002). In subgroup analyses, the need for IMV was significantly lower in the NHFOV group than in the NCPAP and NIPPV group (7 : 79 vs. 15 : 74; 95% CI: 1.00-6.836; p = 0.044 and 11 : 102 vs. 22 : 98; 95% CI: 1.092-5.251; p = 0.026), and there was no difference between NIPPV and NCPAP in the preterm infants at ≤ 32 weeks' gestational age. There were no significant differences among three groups (p > 0.05 respectively) regarding secondary outcomes. In this multicenter retrospective cohort study, NHFOV significantly reduced the need for IMV within the first 7 days as compared to NCPAP and NIPPV in the treatment of preterm infants with RDS without increasing the incidence of adverse events. However, NIPPV was not found to be superior to NCPAP for decreasing the need for IMV in the treatment of preterm infants with RDS. Copyright: © 2020 Termedia & Banach.