BACKGROUND Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is an effective rescue therapy for improving oxygenation in selected severe acute respiratory distress syndrome (ARDS). Prone position (PP) is usually considered before vvECMO and few data are available on the association of PP during VV-ECMO. Thus, we investigated the effect on oxygenation and the safety of PP during vvECMO. METHODS During a two-year period, 15 patients with severe ARDS were turned into PP during VV-ECMO therapy for at least one of the three following conditions: severe hypoxemia (PaO2/FiO2 ratio below 70) despite maximal oxygenation, injurious ventilation parameters with plateau pressure exceeding 32 cmH2O or failure of attempt to wean ECMO after at least 10 days on ECMO support. RESULTS PP was considered after a median of 9 days of ECMO and applied for a median of 12 hours and an average of 1.4 sessions per patient resulting in a total of 21 procedures. We found significant improvement in PaO2/FiO2 ratio at 6 hours (P=0.03) and 12 hours (P=0.007) after reversal. The improvement in oxygenation has still persisted 1hour (P=0.017) and 6 hours (P=0.013) after back to the supine position. No change in PaCO2, respiratory system (RS) compliance was observed. ECMO flow was maintained constant during the procedure. No complication related to PP was detected. CONCLUSIONS PP may be considered in selected patients difficult to wean or remaining very hypoxemic despite VV-ECMO support.