Background Non-invasive ventilation is increased used in preterm infants. We aimed to compare the effectiveness of nasal intermittent positive pressure ventilation (nIPPV) versus nasal continuous positive airway pressure (nCPAP) in preterm infants with respiratory distress syndrome (RDS) after less invasive surfactant administration (LISA). Materials and Methods In this clinical trial, eighty two preterm infants admitted in neonatal intensive care unit, Sohag University Hospital, Egypt with a gestational age of 28–34 weeks, mean ± standard deviation birth weight (1259.44±377.22 grams), suffering from RDS but not requiring intubation in the delivery room were included in the study. Forty one received nIPPV as an initial respiratory support (RS). If nIPPV failed, surfactant administration was given with the LISA approach and patients continued on nIPPV. This group was compared with a historical cohort group of 41 infants managed with nCPAP as an initial RS, and if nCPAP failed, the surfactant was given by LISA. Results There was no significant difference between the case and control group regarding the mean ± SD gestational age or birth weight. When nIPPV was used as the primary RS in preterm infants with RDS compared to nCPAP, it had a significantly less nIPPV failure (31.71% versus 53.66%, P = 0.04), had significantly fewer infants who needed invasive ventilation within the first seven days of life (12.20% versus 34.14%, P = 0.03), and the total days of supplemental oxygen was less (9 (3–18) days versus 12 (6–34) days, P = 0.02). Conclusion In infants born at 28–34 weeks gestation, nIPPV, when used as the primary RS, reduced the need for invasive ventilation and the surfactant requirement within the LISA technique.