Background <p>In mechanically ventilated patients with acute respiratory distress syndrome (ARDS) it is of great importance to prevent ventilator-induced lung injury (VILI) using lung protective ventilation. VILI has been associated with a high mechanical power (MP). Flow-controlled ventilation (FCV) could play a role in decreasing the risk of VILI by lowering the MP and preventing atelectrauma by a controlled expiration.</p> Objectives <p>To assess the difference in MP between FCV and pressure-controlled ventilation (PCV). Secondary aims were to explore the effect of FCV in terms of ventilation distribution and homogeneity, measured by electrical impedance tomography (EIT).</p> Methods <p>Randomized crossover physiological pilot study in ICU patients with a moderate to severe ARDS. Patients were randomized between 90 min of FCV followed by 90 min of PCV, or vice versa. Intratracheal and esophageal pressure, airway flow and EIT were measured continuously, and hemodynamics and venous and arterial blood gases were obtained repeatedly. Pressure–volume loops were constructed for the calculation of the MP.</p> Results <p>In 10 patients, optimized FCV (compliance-guided driving pressure) versus PCV resulted in a similar MP (12.6 vs. 14.8 J/min; <i>p</i> = 0.302). A stable gas exchange at similar minute volumes was obtained. Optimized FCV resulted in increased tidal ventilation of the mid-ventral to dorsal regions compared to PCV, but EIT demonstrated a trend towards overdistension especially of the non-dependent lung regions. Because of this trend towards overdistension, severe hypercapnia in one patient, and inability to apply FCV as intended, the study was stopped early due to safety concerns.</p> Conclusions <p>Optimized FCV compared with PCV resulted in a similar MP and tends towards overdistension in patients with moderate to severe ARDS.</p> Trial registration <p>Clinicaltrials.gov identifier: NCT06051188. Registered 22 September 2023.</p>