Rationale: Changes in oxygenation are often used to guide the recruitment procedure during open lung high-frequency ventilation in preterm infants. However, data on the feasibility and safety of this approach in daily clinical practice are limited. Objective: To prospectively collect data on ventilator settings, gas exchange and circulatory parameters before and after surfactant therapy during open lung high-frequency ventilation. Methods: In 103 preterm infants with respiratory distress syndrome the opening, closing and optimal pressure was determined during high-frequency ventilation by stepwise increasing and decreasing the continuous distending pressure, defining optimal recruitment as adequate oxygenation using a fraction of inspired oxygen 0.25. This procedure was repeated after each surfactant treatment. Measurements and main results: The mean presurfactant opening and optimal continuous distending pressure were respectively, 20.5 ± 4.3 and 14.0 ± 4.0 cmH₂O, with a fraction of inspired oxygen of 0.24 ± 0.04. Surfactant treatment enabled a reduction in the mean optimal pressure of almost 6 cmH₂O without compromising oxygenation. Blood pressure and heart rate remained stable and no air leaks were observed during the recruitment procedures. The mortality rate, the incidence of severe intracranial hemorrhage or periventricular leukomalacia and chronic lung disease at 36 wk was comparable to previously reported data. Conclusion: Open lung high-frequency ventilation using oxygenation to guide the recruitment process is feasible and safe in preterm infants and enables a reduction of the fraction of inspired oxygen below 0.25 in the majority of preterm infants with respiratory distress syndrome.