© 2017 Daedalus Enterprises. BACKGROUND: Mid-frequency ventilation, a strategy of using conventional ventilators at high frequencies, may reduce lung injury but has had limited evaluation in neonates. Hence, a randomized crossover study was designed to assess the feasibility of using mid-frequency ventilation in preterm infants with respiratory distress syndrome. METHODS: Twelve preterm infants (>500 g and >24 weeks gestational age) who were receiving pressure-limited conventional ventilation with frequencies <60 breaths/min for respiratory distress syndrome were randomized to periods of mid-frequency ventilation (conventional ventilation with the fastest frequency up to 150 breaths/min that gave complete inspiration and expiration) or conventional ventilation (frequency <60 breaths/min), each lasting 2 h using a crossover design. Ventilator parameters were adjusted to maintain the O2 saturation and transcutaneous CO2 at baseline. RESULTS: Mean peak inspiratory pressure (15 = 4 cmH2Ovs 18 = 4 cmH2O, P <. 001), Δ pressure (9.8 = 3.3 cm H2O vs 13.5 = 3.9 cm H2O, P <. 001), and tidal volume (2.6 = 0.4 mL/kg vs 4.6 = 0.8 mL/kg, P <. 001) were lower, but mean airway pressure (8.9 = 1.9 cm H2O vs 8.4 = 1.6 cm H2O, P =. 02) and measured PEEP (5.1 = 0.5 cm H2O vs 4.4 = 0.5 cm H2O, P <. 001) were higher with mid-frequency compared with conventional ventilation. FIO2, gas exchange, and hemodynamic parameters were not affected. CONCLUSIONS: Based on this small study, mid-frequency ventilation among preterm infants with respiratory distress syndrome is feasible. Further larger and longer duration trials are necessary to validate our findings. (ClinicalTrials.gov registration NCT01242462).