Aim:This study aimed to compare the effectiveness of Heated Humidified High-Flow Nasal Cannula (HHHFNC) and Continuous Positive Airway Pressure (CPAP) in neonates with respiratory distress syndrome (RDS) regarding treatment success, duration of respiratory support, complications, and treatment failure rates. Materials and Methods:This prospective, randomized comparative trial included 100 neonates diagnosed with RDS. The neonates were randomly assigned to two groups: HHHFNC (n=50) and CPAP (n=50). Both groups received non-invasive respiratory support within 24 hours of birth. Primary outcomes included treatment success, defined as RDS resolution without invasive ventilation, and secondary outcomes involved duration of respiratory support, hospital stay, and incidence of complications such as nasal trauma, pneumothorax, bronchopulmonary dysplasia (BPD), and intraventricular hemorrhage (IVH). Data were analyzed using independent t-tests, chi-square tests, and multivariate logistic regression. Results:The HHHFNC group had a significantly shorter duration of respiratory support (48.5 ± 12.4 hours vs. 52.6 ± 14.1 hours, p = 0.045) and hospital stay (12.6 ± 3.8 days vs. 14.1 ± 4.2 days, p = 0.032) compared to the CPAP group. Nasal trauma was more frequent in the CPAP group (20% vs. 8%, p = 0.067). Treatment failure rates were 12% in the HHHFNC group and 20% in the CPAP group (p = 0.224), with no significant difference in overall treatment success (88% vs. 80%, p = 0.224). Other complications, such as pneumothorax, BPD, IVH, and sepsis, were comparable between the groups. Conclusion:Both HHHFNC and CPAP are effective for managing RDS in neonates. HHHFNC offers advantages in terms of reduced nasal trauma and shorter hospital stays, making it a viable alternative to CPAP for mild to moderate RDS. CPAP remains more effective in maintaining airway pressure for severe cases. Further research is needed to determine optimal use based on clinical scenarios.