Objective:To measure the efficacy and safety of surfactant administered by MIST and INSURE to neonates with respiratory distress syndrome.Methods:A randomized controlled trial was conducted from June 2021 to August 2022 at the NICU of the University of Child Health Sciences, Lahore. Neonates meeting inclusion criteria i.e with RDS who worsened on nasal Continuous positive airway pressure (nCPAP) (fiO2 30%, pressure 6cmH2O) were enrolled in the study in both interventional arms (MIST, n=36 and INSURE, n=36) using simple random sampling. Data was analysed using SPSS 25.Results:The mean age of neonates in MIST was 1.27±0.40 days and 1.23±0.48 days in INSURE cohort. Neonates with MIST (n=8) required statistically significant reduced need for IMV than INSURE (n=17) technique (P-Value 0.047). This study could not achieve significant difference in duration of mechanical ventilation (1±1.67; 1.52±1.40 days, P=0.152) and duration of nCPAP (3.27±1.65;3.67±1.64 hrs, P=0.312) in MIST versus INSURE. The second dose of surfactant was administered in fewer cases in MIST (n=2) than INSURE (n=7) (P=0.075). Risk estimation, although not significant, determined less likelihood for the pulmonary haemorrhage (0.908 than 1.095), intraventricular hemorrhage (0.657 than 1.353), administration of the second dose of surfactant (0.412 than 1.690) and greater likelihood of discharge (1.082 than 0.270) at 95% confidence interval with MIST technique.Conclusion:Surfactant therapy through MIST is effective and there is significantly reduced need of IMV than in INSURE. Safety profile though could not achieve statistical significance yet determines less risk of complications associated with MIST than INSURE.RCT Registration Number:TCTR20210627001