Red blood cell (RBC) transfusion is used in the critically ill with low hemoglobin concentrations to optimize oxygen utilization and delivery imbalance. Data suggest that RBC transfusion is also independently associated with significant morbidity. We seek to characterize RBC transfusion volumes among patients receiving extracorporeal membrane oxygenation (ECMO) support and test the hypothesis that red blood cell transfusion volume is an independent risk factor for mortality. Records of all patients receiving ECMO support from 2001 through 2010 at a university-affiliated children's hospital were retrospectively reviewed. Among 484 ECMO runs reviewed, indications for ECMO were classified as cardiac (40%), non-cardiac (42%) or institution of ECMO during cardiopulmonary resuscitation (CPR) (18%). Median duration of ECMO support was 4.6 days, with overall survival to hospital discharge significantly higher among non-cardiac patients (60%) relative to patients supported for cardiac (37%) or external CPR (ECPR) indications (34%, p<0.001). Median RBC transfusion volumes with respect to ECMO indication were significantly greater among cardiac (105 mL/kg/day ECMO) and ECPR patients (66 mL/kg/day ECMO) relative to patients supported for non-cardiac indications (20 mL/kg/day ECMO, p<0.001). Among patients supported with ECMO for non-cardiac indications alone (n=203), independent of covariates, including weight, venoarterial mode of ECMO support, presence of congenital diaphragmatic hernia and complications, including hemorrhage, neurologic injury, and renal insufficiency, each RBC transfusion volume of 10 mL/kg/day ECMO was associated with a 24% increase in the odds of in-hospital mortality (OR 1.024, 95% CI 1.004-1.046, p=0.018). Greater red blood cell transfusion volumes among patients supported with ECMO for non-cardiac indications are independently associated with an increase in odds of mortality. A prospective investigation of restrictive RBC transfusion practices while receiving ECMO may be warranted in this population.