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To assess long-term survival in adult patients with severe acute lung failure receiving veno-venous extracorporeal membrane oxygenation and explore risk factors for long-term mortality.Single-center prospective cohort study.University Hospital Regensburg, Germany.All primary cases supported with veno-venous extracorporeal membrane oxygenation from 2007 to 2016 (n = 553).None.Patients were followed until January 2017. Long-term survival and predictors of long-term mortality were assessed using Kaplan-Meier survival analyses and Cox proportional hazards modeling, respectively. Two hundred eighty-six patients (52%) died during follow-up (mean follow-up 4.8 yr). Two hundred seventeen patients (39%) died during hospitalization, whereas another 69 patients (12%) died during later follow-up. Among hospital survivors, the 1-month, 3-month, 1-year, and 5-year survival rates were 99%, 95%, 86%, and 76%, respectively. Higher age, immunocompromised status, and higher Sequential Organ Failure Assessment scores were associated with long-term mortality, whereas patients with out-of-center cannulation showed improved long-term survival. Due to nonproportional hazards over time, the analysis was repeated for hospital survivors only (n = 336). Only age and immunocompromised state remained significant predictors of late mortality among hospital survivors. Lower Glasgow Outcome Scale at hospital discharge and the University Hospital Regensburg pre–extracorporeal membrane oxygenation score for predicting hospital mortality in veno-venous extracorporeal membrane oxygenation patients before extracorporeal membrane oxygenation initiation were associated with late mortality in hospital survivors (p < 0.001).Whereas acute illness factors may be important in prediction of hospital outcomes in veno-venous extracorporeal membrane oxygenation patients, they do not determine late mortality in hospital survivors. Preexisting morbidity and functional ability at hospital discharge may be important determinants of long-term survival in veno-venous extracorporeal membrane oxygenation patients.