In critically ill patients with moderate to severe acute respiratory distress syndrome (ARDS) receiving invasive mechanical ventilation, prone positioning for 16 hours/day has been shown to confer significant mortality benefit.¹ In the recent European Society of Intensive Care Medicine (ESICM) clinical practice guidelines on ARDS respiratory support strategies, routine prone positioning is strongly recommended.² The improvement in gas exchange observed following prone positioning however, does not predict improved survival, further supporting the theory that the likely mechanism of benefit of lung protective (low-volume, low-pressure) ventilation in prone position is further reduction in ventilator-induced lung injury (VILI) through improvement in pulmonary mechanics.³ Veno-venous extracorporeal membrane oxygenation (VV ECMO) is part of the management algorithm for patients with severe ARDS in whom adequate gas exchange cannot be maintained at noninjurious levels of ventilation.⁴ Veno-venous extracorporeal membrane oxygenation facilitates ultra-lung protective ventilation allowing for reduction in tidal volumes, driving pressure, and mechanical power further mitigating VILI.⁵ Significant reduction in ventilatory pressures however, may lead to atelectrauma which can contribute to VILI. The combination of VV ECMO and prone positioning is thought to reduce atelectrauma and potentially mitigate further VILI, and data from observational studies, conventional, and individual patient meta-analyses have previously suggested outcome benefit.^6–9 However, the recently published PRONECMO randomized trial comparing early prone positioning with usual care in patients with severe coronavirus disease 2019 (COVID-19)-related ARDS receiving VV ECMMO, showed that prone positioning was safe but did not improve survival at 60 and 90 days, and did not significantly reduce time-to-liberation from ECMO.¹⁰ The difference in results between the observational studies and PRONECMO may be explained by the fact that PRONECMO tested the intervention in a phenotypically heterogeneous population and in essence it was a randomized control trial that almost exclusively recruited patients with COVID-19-related ARDS, making its results nongeneralizable to populations with ARDS of other etiologies.^6–11 In prone positioning research during VV ECMO undertaken so far, the main indication for prone positioning was impaired gas exchange despite VV ECMO, inability to liberate from VV ECMO in the absence of significant lung parenchymal injury or randomization to a prone positioning study group in the context of a randomized controlled trial.^10,12–21