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Objectives: The study investigated the impact of prone positioning during venovenous extracorporeal membrane oxygenation support for coronavirus disease 2019 acute respiratory failure on the patient outcome., Design: An observational study of venovenous extracorporeal membrane oxygenation patients. We used a multistate survival model to compare the outcomes of patients treated with or without prone positioning during extracorporeal membrane oxygenation, which incorporates the dynamic nature of prone positioning and adjusts for potential confounders., Setting: Seventy-two international institutions participating in the Coronavirus Disease 2019 Critical Care Consortium international registry., Patients: Coronavirus disease 2019 patients who were supported by venovenous extracorporeal membrane oxygenation during the study period., Intervention: None., Measurements and Main Results: There were 232 coronavirus disease 2019 patients at 72 participating institutions who were supported with venovenous extracorporeal membrane oxygenation during the study period from February 16, 2020, to October 31, 2020. Proning was used in 176 patients (76%) before initiation of extracorporeal membrane oxygenation and in 67 patients (29%) during extracorporeal membrane oxygenation. Survival to hospital discharge was 33% in the extracorporeal membrane oxygenation prone group versus 22% in the extracorporeal membrane oxygenation supine group. Prone positioning during extracorporeal membrane oxygenation support was associated with reduced mortality (hazard ratio, 0.31; 95% CI, 0.14-0.68)., Conclusions: Our study highlights that prone positioning during venovenous extracorporeal membrane oxygenation support for refractory coronavirus disease 2019-related acute respiratory distress syndrome is associated with reduced mortality. Given the observational nature of the study, a randomized controlled trial of prone positioning on venovenous extracorporeal membrane oxygenation is needed to confirm these findings., Competing Interests: Dr. Jacobs received funding from SpecialtyCare and the American Academy of Dermatology. Dr. Heinsar received funding via PhD scholarship from the University of Queensland. Dr. Bassi’s institution received funding from Fisher & Paykel. Dr. Dalton received funding from Innovative Extracorporeal Membrane Oxygenation (ECMO) Concepts; she disclosed the off-label product use of ECMO equipment. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)