Preterm neonates with respiratory distress syndrome (RDS) are commonly treated with surfactant by intubate surfactant extubate (InSurE) technique. Mode of surfactant administration has evolved towards less invasive technique in the last few years. We randomised 58 preterm infants of 28-34 weeks of gestation with RDS within 6 h of birth to receive surfactant by InSurE or minimally invasive surfactant therapy (MIST). Non-invasive positive pressure ventilation (NIPPV) was used as primary respiratory support. The main objective was to compare the need of invasive mechanical ventilation (IMV) in first 72 h of life and secondarily hemodynamically significant patent ductus arteriosus (hsPDA), intraventricular haemorrhage (IVH) (> grade 2), bronchopulmonary dysplasia (BPD) and composite outcome of BPD/mortality. We did not find any difference in need of IMV in first 72 h between MIST and InSurE (relative risk with MIST, 0.62; 95% confidence interval, 0.22 to 1.32). No difference was observed in terms of hs PDA, IVH (> grade 2), BPD and composite outcome of BPD/mortality.Conclusion: There is no difference between MIST and InSurE in preterm neonates with RDS with NIPPV as a primary mode of respiratory support. Larger multicentre studies are needed to further explore differences in treatment failure and other secondary outcomes.Trial registration: www.ctri.nic.in id CTRI/2019/03/017992, registration date March 8, 2019.What is Known• InSurE is commonly used for many years for treatment of RDS in preterm neonates.• MIST has been introduced as a newer tool.What is New• MIST with feeding tube is comparable with InSurE in preterm infants with RDS in developing countries.•NIPPV can be used as primary respiratory support for MIST.