Objective: To compare the efficacy, need for mechanical ventilation within 72 hours of surfactant administration, and primary and secondary outcomes after LISA and INSURE methods. Methodology: A randomized control study was conducted at NICUs at Medical college, Vadodara, and GMERS, Gotri for a period of 8 months. A total of 40 preterm infants between 28 to 34 weeks of gestation with RDS who required surfactant administration were enrolled and randomized into two groups of 20 patients each. Surfactant was administered by LISA and INSURE method according to randomization. Results: There were 70% male infants in the LISA group, and 55% in INSURE group. Mean GA in the LISA group was 30.3±2.2 weeks, and 30.95±1.88 weeks in INSURE group, and mean birth weight was 1.24±0.3 kg in the LISA group and 1.25±0.3 kg in INSURE group. 40% of patients in LISA and 55% in INSURE group had not received antenatal steroids. Basic characteristics and maternal risk factors were comparable in both groups. Mechanical ventilation was required within 72 hours of surfactant administration in 6 patients (30%) in the LISA group and 14 patients (70%) in INSURE group (p-value = 0.0238). 8 patients (40%) from the LISA group and 16 patients (80%) from INSURE group required mechanical ventilation during their entire NICU stay (p=0.0268). Conclusion: The requirement of mechanical ventilation within 72 hours of surfactant administration as well as during the entire NICU stay was more in INSURE group than the LISA group with a statistically significant difference.