Introduction Most patients on extracorporeal membrane oxygenation (ECMO) decease during therapy on the system. However, the actual causes of death have not been studied sufficiently. This study analyses the etiology, prevalence, and risk factors for the outcome variable death during ongoing ECMO for all patients and divided according to venoarterial (VA) or venovenous (VV) support.Methods We retrospectively analysed all patients receiving ECMO support at our institution between March 2006 to January 2021. Only the patients deceased during ongoing support were included.Results 2016 patients were placed on VA (n = 1168; 58%) or VV (n = 848; 42%) ECMO; 759 patients (37.7%) deceased on support. The causes of death differed between the support types: VA ECMO patients mostly died from cerebral ischemia (34%), low-cardiac output (LCO; 24.1%) and multi-organ failure (MOF; 21.6%), whereas in VV ECMO cases, refractory respiratory failure (28.2%), and sepsis (20.4%) dominated. Multivariate regression analysis revealed cardiopulmonary resuscitation (CPR) and acidosis prior to ECMO as risk factors for dying on VA ECMO, while high inotropic doses pre-ECMO, a high fraction of inspired oxygen on day 1, elevated lactate dehydrogenase, and international normalized ratio levels lead to an unfavourable outcome in VV ECMO patients.Conclusion Even in highly experienced centers, ECMO mortality remains high and occurs mainly on support or 24 h after its termination. The causes of death differ between VV and VA ECMO, depending on the underlying diseases responsible for the need of extracorporeal support.