Abstract: Objective To observe the effect of minimally invasive surfactant therapy in the treatment of premature infants with respiratory distress syndrome. Methods Sixty premature infants with RDS hospitalized in the Neonatal Intensive Care Unit(NICU) of the First Affiliated Hospital of Bengbu Medical College from January 2018 to March 2019 were randomly divided into MIST group(30 cases) using minimally invasive pulmonary surfactant application technology and INSURE group(30 cases) using intubation-PS-extubation by nasal positive airway pressure ventilation. The relevant clinical data were collected and analyzed. The oxygen metabolism index, secondary PS application, pneumothorax, bronchopulmonary dysplasia(BPD), mortality rate, the proportion of mechanical ventilation within 72 hours, and hospitalization time were compared. Results At 6, 12, 24 and 48 hours, FiO₂, PaO₂, P/F, PaO₂/PAO₂ in MIST group were significantly less than those in INSURE group, while PEEP/EPAP and PaCO₂ in MIST group were significantly higher than those in INSURE group. There were significant differences in secondary PS application rate(3.33% vs. 20.00%), pneumothorax(0.00% vs.16.67%) and hospitalization time between two groups(all P<0.05). There were no significant differences in 72 h mechanical ventilation(0.00% vs.3.33%), BPD(0.00% vs.3.33%) between MIST group and INSUR group,there was no death in two groups. Conclusion Minimally invasive pulmonary surfactant therapy can significantly improve oxygen metabolism, reduce secondary PS application and pneumothorax ratio, shorten hospitalization time and improve the prognosis of premature infants with RDS.