ObjectiveTo perform a network meta-analysis of randomised controlled trials of different surfactant treatment strategies for respiratory distress syndrome (RDS) to assess if a certain fraction of inspired oxygen (FiO₂) is optimal for selective surfactant therapy.DesignSystematic review and network meta-analysis using Bayesian analysis of randomised trials of prophylactic versus selective surfactant for RDS.SettingCochrane Central Register of Controlled Trials, MEDLINE, Embase and Science Citation Index Expanded.PatientsRandomised trials including infants under 32 weeks of gestational age.InterventionsIntratracheal surfactant, irrespective of type or dose.Main outcome measuresOur primary outcome was neonatal mortality, compared between groups treated with selective surfactant therapy at different thresholds of FiO₂. Secondary outcomes included respiratory morbidity and major complications of prematurity.ResultsOf 4643 identified references, 14 studies involving 5298 participants were included. We found no statistically significant differences between 30%, 40% and 50% FiO₂thresholds. A sensitivity analysis of infants treated in the era of high antenatal steroid use and nasal continuous positive airway pressure as initial mode of respiratory support showed no difference in mortality, RDS or intraventricular haemorrhage alone but suggested an increase in the combined outcome of major morbidities in the 60% threshold.ConclusionOur results do not show a clear benefit of surfactant treatment at any threshold of FiO₂. The 60% threshold was suggestive of increased morbidity. There was no advantage seen with prophylactic treatment. Randomised trials of different thresholds for surfactant delivery are urgently needed to guide clinicians and provide robust evidence.PROSPERO registration numberCRD42020166620.