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Background: Among respiratory support techniques, nasal continuous positive airway pressure (NCPAP) and mechanical ventilation (MV) are more known for their effectivity in reducing complications associated with respiratory distress syndrome (RDS). Moreover, early application of NCPAP and administration of surfactant are effective in decreasing the need for MV and its adverse effects. This study was designed to compare NCPAP and MV after administration of surfactant in preterm neonates with RDS. Materials and Methods: In this clinical trial, 60 preterm neonates (<32 weeks) were evaluated. After receiving one dose of surfactant (4 cc/kg), the subjects were randomly divided into treatment and control groups, and respiratory support was established via positive airway pressure or MV. Results: There were no significant differences between the neonates in the two groups in terms of gestational age and birth weight. The mean duration of MV was significantly lower in the treatment group (p=0.001). On day 3, the number of ventilator-dependent neonates in the control group was more (26.7% versus 83.3%). There were no significant differences between the two groups in the number of second surfactant doses, mortality rate, and the number of patients who had developed short-term complications during hospital stay. Conclusion: In a significant number of preterm babies with RDS, NCPAP can be extubated after receiving one dose of surfactant. This is a potentially useful modality for respiratory support with a low mortality and morbidity rate and limited complications in very premature infants.