Abstract Background Whether targeting the driving pressure (∆P) when adjusting the tidal volume in mechanically ventilated patients with the acute respiratory distress syndrome (ARDS) may decrease the risk of ventilator-induced lung injury remains a matter of research. In this study, we assessed the effect of a ∆P-guided ventilation on the mechanical power. Methods We prospectively included adult patients with moderate-to-severe ARDS. Positive end expiratory pressure was set by the attending physician and kept constant during the study. Tidal volume was first adjusted to target 6 ml/kg of predicted body weight (PBW-guided ventilation) and subsequently modified within a range from 4 to 10 ml/kg PBW to target a ∆P between 12 and 14 cm H 2 O. The respiratory rate was then re-adjusted within a range from 12 to 40 breaths/min until EtCO 2 returned to its baseline value (∆P-guided ventilation). Mechanical power was computed at each step. Results Fifty-one patients were included between December 2019 and May 2021. ∆P-guided ventilation was feasible in all but one patient. The ∆P during PBW-guided ventilation was already within the target range of ∆P-guided ventilation in five (10%) patients, above in nine (18%) and below in 36 (72%). The change from PBW- to ∆P-guided ventilation was thus accompanied by an overall increase in tidal volume from 6.1 mL/kg PBW 5.9–6.2 to 7.7 ml/kg PBW 6.2–8.7, while respiratory rate was decreased from 29 breaths/min 26–32 to 21 breaths/min 16–28 ( p  < 0.001 for all comparisons). ∆P-guided ventilation was accompanied by a significant decrease in mechanical power from 31.5 J/min 28–35.7 to 28.8 J/min 24.6–32.6 ( p  < 0.001), representing a relative decrease of 7% 0–16. With ∆P-guided ventilation, the PaO 2 /FiO 2 ratio increased and the ventilatory ratio decreased. Conclusion As compared to a conventional PBW-guided ventilation, a ∆P-guided ventilation strategy targeting a ∆P between 12 and 14 cm H 2 O required to change the tidal volume in 90% of the patients. Such ∆P-guided ventilation significantly reduced the mechanical power. Whether this physiological observation could be associated with clinical benefit should be assessed in clinical trials.