The aim of this study was to evaluate the impact of pre-extracorporeal membrane oxygenation (ECMO) ventilatory parameters with in-hospital mortality in children with pediatric acute respiratory distress syndrome undergoing ECMO for respiratory indication. In this retrospective analysis of the Extracorporeal Life Support Organization (ELSO) Registry, all pediatric patients (≥29 days to ≤18 years) who required ECMO for respiratory indications were screened. The primary outcome was in-hospital mortality. From 2013 to 2017, 2,727 pediatric ECMO runs with a respiratory indication were reported to the ELSO registry. Overall mortality was 37%. Oxygenation Index (OI) and duration of mechanical ventilation (MV) before ECMO deployment were both independently associated with in-hospital mortality. No threshold effect for OI was observed. Pre-ECMO positive end-expiratory pressure and delta pressure levels were respectively lower and higher than recommended. Mortality rates for OI values between 4 and 60 and above oscillated between 32% and 45%. Children within a wider range of pre-ECMO OI (either below or above 40) might be considered as reasonable candidates for ECMO deployment. Larger, prospective multicenter studies to confirm the discriminatory ability of OI are warranted.