Background: Although nasal continuous positive airway pressure (NCPAP) in the treatment of respiratory distress syndrome (RDS) is an effective and a non-invasive method, some complications such as septal trauma and intolerance of NCPAP apparatus are occurred. Our objectives are to assess safety and effectiveness of humidified high flow nasal canola (HFNC) as compared to NCPAP in premature neonates with RDS. Methods: Seventy uncomplicated preterm infant (30-35 weeks gestation) with RDS at the neonatal ward of Shahid-Beheshti hospital, Isfahan, Iran, randomized into two groups; Group1 (CPAP) received NCPAP from birth and continued till respiratory distress (RD) and oxygen (O2) need improved and Group 2 (HFNC) received NCPAP for the first 24 hours after birth, then standard HFNC till RD and O2 need improved. Outcomes measures of interest included: death, morbidity such as necrotizing enterocolitis (NEC), patent ductus arteriosus (PDA), (Intraventricular hemorrhage (IVH), chronic lung disease (CLD), pnumothorax, pulmonary hemorrhage, apnea, sepsis, duration of hospitalization, duration of full entral feeding and duration of O2 need. Data entered to computer and outcomes were compared between 2 groups with SPSS software (vesion 11). P values less than 0.05 were considered statistically significant. Findings: There were no differences in death, duration of hospitalization, failure to treatment, duration of improvement of RD, NEC, PDA, IVH, CLD, pnumothorax, pulmonary hemorrhage, apnea, sepsis, duration of hospitalization, duration to reach to full entral feeding between two groups (NCPAP, HFNC). During the study, those on HFNC had more normal examination of nasal mucosa (P < 0.0001). According to neonatal nurses opinions, application of HFNC was easier than NCPAP for neonates (P < 0.0001). Conclusion: HFNC (after received NCPAP for the first 24 hours of birth) is as effective as NCPAP in the management of RDS in premature neonates more than 30 gestational weeks. In addition, HFNC performed easier than NCPAP with maintaining a normal nasal mucosa. [ABSTRACT FROM AUTHOR]