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Extracorporeal membrane oxygenation, an accepted rescue therapy for refractory cardiopulmonary failure, requires a complex multidisciplinary approach and advanced technology. Little is known about the relationship between a center’s case volume and patient mortality. The purpose of this study was to analyze the relationship between hospital extracorporeal membrane oxygenation annual volume and in-hospital mortality and assess if a minimum hospital volume could be recommended.Retrospective cohort study.A retrospective cohort admitted to children’s hospitals in the Pediatric Health Information System database from 2004 to 2011 supported with extracorporeal membrane oxygenation was identified. Indications were assigned based on patient age (neonatal vs pediatric), diagnosis, and procedure codes. Average hospital annual volume was defined as 0–19, 20–49, or greater than or equal to 50 cases per year. Maximum likelihood estimates were used to assess minimum annual case volume.A total of 7,322 pediatric patients aged 0–18 were supported with extracorporeal membrane oxygenation and had an indication assigned.None.Average hospital extracorporeal membrane oxygenation volume ranged from 1 to 58 cases per year. Overall mortality was 43% but differed significantly by indication. After adjustment for case-mix, complexity of cardiac surgery, and year of treatment, patients treated at medium-volume centers (odds ratio, 0.86; 95% CI, 0.75–0.98) and high-volume centers (odds ratio, 0.75; 95% CI, 0.63–0.89) had significantly lower odds of death compared with those treated at low-volume centers. The minimum annual case load most significantly associated with lower mortality was 22 (95% CI, 22–28).Pediatric centers with low extracorporeal membrane oxygenation average annual case volume had significantly higher mortality and a minimum volume of 22 cases per year was associated with improved mortality. We suggest that this threshold should be evaluated by additional study.