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Objectives: To determine whether multisite versus single-site dual-lumen (SSDL) cannulation is associated with outcomes for COVID-19 patients requiring venovenous extracorporeal membrane oxygenation (VV-ECMO)., Design: Retrospective analysis of the Extracorporeal Life Support Organization Registry. Propensity score matching (2:1 multisite vs SSDL) was used to control for confounders., Patients: The matched cohort included 2,628 patients (1,752 multisite, 876 SSDL) from 170 centers. The mean ( sd ) age in the entire cohort was 48 (11) years, and 3,909 (71%) were male. Patients were supported with mechanical ventilation for a median (interquartile range) of 79 (113) hours before VV-ECMO support., Interventions: None., Measurements: The primary outcome was 90-day survival. Secondary outcomes included survival to hospital discharge, duration of ECMO support, days free of ECMO support at 90 days, and complication rates., Main Results: There was no difference in 90-day survival (49.4 vs 48.9%, p = 0.66), survival to hospital discharge (49.8 vs 48.2%, p = 0.44), duration of ECMO support (17.9 vs 17.1 d, p = 0.82), or hospital length of stay after cannulation (28 vs 27.4 d, p = 0.37) between multisite and SSDL groups. More SSDL patients were extubated within 24 hours (4% vs 1.9%, p = 0.001). Multisite patients had higher ECMO flows at 24 hours (4.5 vs 4.1 L/min, p < 0.001) and more ECMO-free days at 90 days (3.1 vs 2.0 d, p = 0.02). SSDL patients had higher rates of pneumothorax (13.9% vs 11%, p = 0.03). Cannula site bleeding (6.4% vs 4.7%, p = 0.03), oxygenator failure (16.7 vs 13.4%, p = 0.03), and circuit clots (5.5% vs 3.4%, p = 0.02) were more frequent in multisite patients., Conclusions: In this retrospective study of COVID-19 patients requiring VV-ECMO, 90-day survival did not differ between patients treated with a multisite versus SSDL cannulation strategy and there were only modest differences in major complication rates. These findings do not support the superiority of either cannulation strategy in this setting., Competing Interests: Dr. O’Gara received funding from Sedana Medical. Dr. Shaefi’s institution received funding from the National Institutes for Health (NIH); they received support for article research from the NIH. Dr. Seethala received funding from BD consulting, LivaNova, and Fresenius Medical Care; he disclosed that he is Chair of the Executive Committee for ECMONet and President-elect from Extracorporeal Life Support Organization. Dr. Faugno received funding from Moderna. Drs. Brodie and Garan received funding from Abiomed. Dr. Brodie received funding from Xenios, Medtronic, Cellenkos, Inspira, and LivaNova. Dr. Garan received funding from NuPulseCV; his institution received funding from Verantos; he received support for article research from Abbott. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)