Background The coronavirus disease MESHD 2019 (COVID-19) pandemic has led to surges in the demand for extracorporeal membrane oxygenation (ECMO) therapy. However, little in-depth evidence is known about the application of ECMO therapy in COVID-19 patients.Methods This retrospective multicenter cohort study included 88 patients who had been diagnosed with COVID-19 and received ECMO therapy at seven designated hospitals in Wuhan, China. The clinical characteristics, laboratory examinations, treatments, and outcomes were extracted from electronic medical records and compared between weaned and non-weaned ECMO patients. The patients were followed until June 30, 2020. Logistic regression analyses were performed to identify the risk factors associated with unsuccessful ECMO weaning. Propensity score matching was used to match patients who received veno-venous ECMO with those who received invasive mechanical ventilation (IMV)-only therapy. The primary endpoint, 120-day all-cause mortality after intensive care unit (ICU) admission during hospitalization, was compared using a mixed-effect Cox model.Results Of 88 patients who received ECMO therapy, 27 and 61 patients were and were not successfully weaned from ECMO, respectively. Additionally, 15, 15, and 65 patients were further weaned from IMV, discharged from hospital, or died during hospitalization, respectively. A lymphocyte count ≤ 0.5 × 109/L and D-dimer concentration > 4 × the upper limit of normal at ICU admission, a peak PaCO2 > 60 mmHg at 24 hours before ECMO initiation, and no tracheotomy performed during the ICU stay were independently associated with lower odds of ECMO weaning. In the propensity score-matched analysis, a mixed-effect Cox model detected a lower hazard ratio for 120-day all-cause mortality after ICU admission during hospitalization in the ECMO group, as compared with the IMV-only group.Conclusion Patients in Wuhan who received ECMO therapy had a relatively high mortality rate. This outcome may be largely attributable to resource-limited situations during the COVID-19 outbreak. In future, the presence of lymphocytopenia and higher D-dimer concentrations at ICU admission and hypercapnia MESHD hypercapnia HP at 24 hours before ECMO initiation could help to identify patients with a poor prognosis. Moreover, tracheotomy could facilitate weaning from ECMO. Despite the high mortality, ECMO was associated with improved outcomes relative to IMV-only therapy in critically ill COVID-19 patients.