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Extracorporeal Membrane Oxygenation (ECMO) is associated with significant mortality. Provision of high-quality end-of-life (EOL) care for patients supported on ECMO entails specific physiological, pharmacological, and technical considerations. Limited guidance exists for clinicians on delivery of optimal EOL care on ECMO. In this article, we review the unique aspects of EOL care as they apply to ECMO support and propose a pragmatic, interdisciplinary framework for compassionate ECMO discontinuation in children and adults.