Objective:To compare the efficacy and safety of bi-level positive airway pressure (BiPAP) ventilation and heated humidified high flow nasal cannula (HHHFNC) ventilation as initial respiratory support for premature infants with respiratory distress syndrome (RDS).Methods:From January 2019 to June 2021, premature infants [gestational age (GA) 28~35 weeks)] with grade Ⅰ to Ⅲ RDS admitted to Suining County People's Hospital were prospectively enrolled. The infants were randomly assigned into BiPAP group and HHHFNC group. The clinical characteristics, ventilation efficacy and complications were analyzed.Results:A total of 33 infants were in BiPAP group and 32 in HHHFNC group. No significant differences existed between the two groups in the following items: the frequency of apnea within 24 h of ventilation, FiO 2 and PaCO 2 at 24 h, the use of pulmonary surfactant (PS), the incidence of non-invasive ventilation failure within 72 h, non-invasive ventilation duration and the age achieving total enteral nutrition. HHHFNC group had lower score in premature infants pain profile (PIPP) than BiPAP group at 24 h of non-invasive ventilation [4 (3, 6) vs. 8 (6, 11), P<0.001]. No significant differences existed in nasal injury, pneumothorax, intraventricular hemorrhage, necrotizing enterocolitis, bronchopulmonary dysplasia and mortality rate between the two groups ( P>0.05). Conclusions:As the initial treatment for premature infants with grade Ⅰ to Ⅲ RDS, BiPAP and HHHFNC has similar rates of non-invasive ventilation failure within 72 h,non-invasive ventilation duration and adverse events. HHHFNC may ease the pain of the infants.