ObjectiveThis randomised study in preterm infants on non-invasive respiratory support investigated the effectiveness of automated oxygen control (A-FiO2) in keeping the oxygen saturation (SpO2) within a target range (TR) during a 28-day period compared with manual titration (M-FiO2).DesignA single-centre randomised control trial.SettingA level III neonatal intensive care unit.PatientsPreterm infants (<28 weeks’ gestation) on non-invasive respiratory support.InterventionsA-FiO2versus M-FiO2control.MethodsMain outcomes were the proportion of time spent and median area of episodes in the TR, hyperoxaemia, hypoxaemia and the trend over 28 days using a linear random intercept model.Results23 preterm infants (median gestation 25.7 weeks; birth weight 820 g) were randomised. Compared with M-FiO2, the time spent within TR was higher in the A-FiO2group (68.7% vs 48.0%, p<0.001). Infants in the A-FiO2group spent less time in hyperoxaemia (13.8% vs 37.7%, p<0.001), but no difference was found in hypoxaemia. The time-based analyses showed that the A-FiO2efficacy may differ over time, especially for hypoxaemia. Compared with the M-FiO2group, the A-FiO2group had a larger intercept but with an inversed slope for the daily median area below the TR (intercept 70.1 vs 36.3; estimate/day −0.70 vs 0.69, p<0.001).ConclusionA-FiO2control was superior to manual control in keeping preterm infants on non-invasive respiratory support in a prespecified TR over a period of 28 days. This improvement may come at the expense of increased time below the TR in the first days after initiating A-FiO2control.Trial registration numberNTR6731.