Background: Surfactant therapy represents the cornerstone in treating respiratory distress syndrome (RDS). Different methods have been implicated for surfactant administration in the last few years. Objective: This study aimed to compare the use of surfactant therapy in the intubate, surfactant, extubate (INSURE) technique with surfactant- conventional mechanical ventilation (CMV) modality. Patients and methods: A retrospective comparative study conducted between January 2015 and January 2021 at Minia university hospital for obstetrics and children included 68 preterm infants with respiratory distress syndrome treated with surfactants. They are categorized into two groups: group I included 34 preterm neonates treated by INSURE technique then continuous positive airway pressure (CPAP) and group II: included 34 preterm neonates treated by (surfactant- CMV) using mechanical ventilation. Preterm infants' demographic data, arterial blood gases, oxygen indices, response to treatment, duration of ventilation, hospital stay, and the number of surfactant doses were analyzed and compared.  Results: Treatment was successful in 85.29% of INSURE-.CPAP compared to 79.42% in the surfactant-CMV group. Respiratory indices such as arterial/alveolar oxygen ratio(a/APO2) were significantly low and alveolar /arterial gradient (AaDo2) was significantly high in surfactant- CMV group, Down's score, the number of surfactant doses, duration of ventilation, and hospital stay all were significantly reduced in INSURE-CPAP group. Conclusions: INSURE- CPAP technique is a reliable and effective method for the treatment of RDS, especially in cases with high arterial alveolar ratio (a/APO2) and low arterial oxygen gradient (AaDO2).