Objective Surfactant and noninvasive ventilation are two major strategies for the treatment of neonates with respiratory distress syndrome (RDS). However, the optimal time for surfactant administering is yet controversial. This study compared the early and rescue Calsurf administration in preterm infants with RDS. Study Design Preterm infants born between 26 (0/7) and 32 (6/7) weeks of gestation and needed nasal continuous positive airway pressure (nCPAP) immediately after birth were randomly assigned to the early or rescue Calsurf treatment group. In the early treatment group, neonates were intubated, administered surfactant with bag-mask ventilation, and extubated to nCPAP (INSURE [intubation-surfactant-extubation]). In the rescue treatment group, InSurE was given until the clinical manifestation and chest X-ray displayed RDS. The primary outcome was to compare the reintubation rate within 72 hour age between the two groups. Results Among 305 neonates randomized to the early ( n = 154) and rescue ( n = 151) groups, the reintubation rate within 72 hours of age in these two groups did not differ significantly ( p > 0.05). The incidence of oxygen dependence until 36 weeks' corrected age was similar in both groups. Conclusion No differences were observed between early and rescue Calsurf treatment groups with respect to the reintubation rate within 72 hours of age and the incidence of bronchopulmonary dysplasia.