Bleeding is the most common complication during extracorporeal membrane oxygenation (ECMO). It is associated with an increased mortality and represents the most frequent cause of preliminary ECMO termination. We performed a retrospective analysis in a single ECMO referral center delineating the risk factors and therapeutic interventions of bleeding during adult ECMO in a total of 59 patients. The median length of ECMO support was 158 hours, with an all-cause mortality of 41%. Bleeding occurred on 40% of the days. On multivariate analysis, fungal pneumonia was the only significant factor associated with the occurrence of a bleeding event. The most common bleeding locations were the ECMO cannulation sites. Termination of ECMO support was the most successful therapeutic intervention, followed by the administration of tranexamic acid, replacement of the membrane oxygenator or the ECMO system, administration of factor VIIa, and repositioning of at least one ECMO cannula. Moreover, the transfusion of platelets was a successful mean, as well as the utilization of desmopressin to enhance platelet function. As such, further delineation of the coagulation disorders during ECMO support to provide a sophisticated pharmacotherapy may stop this serious adverse event.