OBJECTIVES: To report current practices regarding mechanical ventilation in patients treated with extracorporeal membrane oxygenation (ECMO) for severe acute respiratory distress syndrome (ARDS) and their association with 6-month outcomes. METHODS: International, multi-center, prospective cohort study of patients undergoing ECMO for ARDS during a one-year period in 23 international intensive care units (ICUs). MEASUREMENTS AND MAIN RESULTS: We collected demographics, daily pre- and per-ECMO mechanical ventilation settings and use of adjunctive therapies, ICU- and 6-month-outcome data for 350 patients (median ± standard deviation pre-ECMO PaO2/FiO2 71±34 mmHg). Pre-ECMO use of prone positioning and neuromuscular blockers were 26% and 62%, respectively. Tidal volume (6.4±2.0 vs 3.7±2.0 ml/kg), plateau pressure (32±7 vs 24±7cmH2O), driving pressure (20±7 vs. 14±4 cmH2O), respiratory rate (26±8 vs 14±6 breaths/min) and mechanical power (26.1±12.7 vs. 6.6±4.8 J/min) were markedly reduced after ECMO initiation. Six-month survival was 61%. No association was found between ventilator settings during the first 2 days of ECMO and survival in multivariable analysis. A time-varying Cox model retained older age, higher fluid balance, higher lactate, and more need for renal replacement therapy along the ECMO course as being independently associated with 6-month mortality. A higher tidal volume and lower driving pressure (likely markers of static compliance improvement) across the ECMO course were also associated with better outcomes. CONCLUSION: Ultra-protective lung ventilation on ECMO was largely adopted across medium to high case-volume ECMO centers. In contrast with previous observations, mechanical ventilation settings during ECMO did not impact patients' prognosis in this context.