Less invasive surfactant administration (LISA) has become increasingly popular in neonatal intensive care units (NICUs), but there are currently no guidelines for the premedication prior to this procedure. The aim of this observational study was to compare the efficacy and tolerance of intravenous administrations of ketamine and propofol before LISA in neonates born before 30 weeks of gestational age (GA). The primary outcome was requirement of intubation within 2 h of the procedure. One hundred and fourteen infants, with respective GA and birthweight of 27.6 (26.4, 28.7) weeks and 940 (805, 1140) g, were prospectively included from January 2016 to December 2019. Drug doses were 1 (0.5, 1) mg/kg for ketamine and 1 (1, 1.9) mg/kg for propofol, providing comparable comfort during LISA (p = 0.61). Rates of intubation within 2 h were 5/52 after ketamine, and 5/62 after propofol [aOR 0.54 (0.11–2.68)]. No difference was observed for rates of intubation at 24 h and 72 h following LISA, mortality, or severe morbidity.Conclusion: Pending results from prospective trials, these findings suggest that ketamine or propofol can be used for premedication before LISA, as they show comparable efficacy and tolerance.Trial registration: This study was recorded on the National Library of Medicine registry (https:// clinicaltrials.gov/ Identifier: NCT03705468).[Table Removed]