PURPOSE: Extracorporeal membrane oxygenation (ECMO) is a refractory treatment for acute respiratory distress syndrome (ARDS) due to influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, also referred to as coronavirus disease 2019 [COVID-19]). We conducted this study to compare the outcomes of influenza patients treated with veno-venous-ECMO (VV-ECMO) to COVID-19 patients treated with VV-ECMO, during the first wave of COVID-19. METHODS: Patients in our institution with ARDS due to COVID-19 or influenza who were placed on ECMO between August 1, 2010 and September 15, 2020 were included in this comparative, retrospective study. To improve homogeneity, only VV-ECMO patients were analyzed. The clinical characteristics and outcomes were extracted and analyzed. RESULTS: A total of 28 COVID-19 patients and 17 influenza patients were identified and included. ECMO survival rates were 68% (19/28) in COVID-19 patients and 94% (16/17) in influenza patients (p = .04). Thirty days survival rates after ECMO decannulation were 54% (15/28) in COVID-19 patients and 76% (13/17) in influenza patients (p = .13). COVID-19 patients spent a longer time on ECMO compared to flu patients (21 vs. 12 days; p = .025), and more COVID-19 patients (26/28 vs. 2/17) were on immunomodulatory therapy before ECMO initiation (p < .001). COVID-19 patients had higher rates of new infections during ECMO (50% vs. 18%; p = .03) and bacterial pneumonia (36% vs. 6%; p = .024). CONCLUSIONS: COVID-19 patients who were treated in our institution with VV-ECMO had statistically lower ECMO survival rates than influenza patients. It is possible that COVID-19 immunomodulation therapies may increase the risk of other superimposed infections.