Background <p>Respiratory distress syndrome is one of the common causes of putting preterm infants on mechanical ventilation. NHFOV and NIPPV are non-invasive ventilatory modalities that can be used post-extubation. NHFOV is a new mode that combines the benefits of continuous positive airway pressure and high frequency ventilation. NIPPV is a time-cycled, pressure-limited mode that can be provided by a conventional ventilator via bi-nasal prongs.</p> Aim of the work <p>To compare between NHFOV and non-synchronized NIPPV post-extubation in preterm infants regarding efficacy and their possible complications.</p> Methods <p>This randomized controlled study (NCT06620107) was conducted on eighty preterm neonates with a gestational age of 32 to 36&#xa0;weeks suffering from respiratory distress syndrome on mechanical ventilation and ready for extubation, randomized to NHFOV (<i>n</i> = 40) and non-synchronized NIPPV (<i>n</i> = 40), followed up for the need of re-intubation, duration of respiratory support and occurrence of complications.</p> Results <p>There was no significant difference between the NHFOV and NIPPV groups as regards the need for re-intubation, while the duration of respiratory support was significantly prolonged in the NIPPV group. There was no significant difference between the two groups as regards the secondary outcomes except for the duration of hospitalization which was significantly prolonged in the NIPPV group.</p> Conclusion <p>Nasal high frequency oscillation ventilation did not decrease the rate of re-intubation in comparison to non-synchronized NIPPV when used as post-extubation support in preterm infants, while it was promising at improving gas exchange and reducing the duration of respiratory support and it showed a comparable safety to NIPPV.</p> Trial registration <p>ClinicalTrials.gov identifier: NCT06620107.</p>