We aimed to determine whether an early prophylactic INSURE strategy combined with early nasal continuous positive airway pressure (nCPAP) treatment could decrease the subsequent need for mechanical ventilation (MV) compared to the administration of surfactant prophylaxis later, at the 15th minute after birth, combined with early nCPAP. Infants born at <30 weeks' gestation were randomized to receive surfactant prophylaxis immediately or at the 15th minute after birth. All infants received 100 mg/kg poractant alpha, were ventilated with a T-piece resuscitator and were extubated to nCPAP if they had sufficient respiratory drive. Forty infants were analyzed in each group. Ten (25%) infants in the early prophylactic INSURE group, and 13 (32.5%) infants in the later prophylactic INSURE group could not be extubated after surfactant administration in the delivery room. Among the infants who were initially extubated to nCPAP after surfactant administration, 6 in the early prophylactic INSURE group and 4 in the later prophylactic INSURE group needed intubation for MV within the first 3 days of life (20% vs. 16.7%; P=0.73). The duration of total respiratory support (CPAP plus MV) of infants who were intubated within the first 3 days of life was shorter in the early prophylactic INSURE group than in the later prophylactic INSURE group (median: 96 h vs. 309 h; P=0.038). The incidence of all neonatal morbidities and mortality and the duration of hospitalization were similar between the groups. Our study did not demonstrate superiority of early surfactant prophylaxis combined with early nCPAP to the later administration of prophylactic surfactant with early nCPAP; however, it did detect an absolute difference in the primary outcome: need for MV within the first 3 days of life.