BACKGROUND: Intracranial hemorrhage (ICH) is a recognized complication of adults treated with extracorporeal membrane oxygenation (ECMO) and is associated with increased morbidity and mortality. However, the predictors of ICH in this patient category are poorly understood. The purpose of this study was to identify predictors of ICH in ECMO-treated adult patients. METHODS: We conducted a retrospective review of adult patients (≥18 years) treated with ECMO at the Karolinska University Hospital (Stockholm, Sweden) between September 2005 and June 2016, excluding patients with ICH upon admission or those who were treated with ECMO for less than 12 h. In a comparative analysis, the primary end-points were the difference in baseline characteristics and predictors of hemorrhage occurrence (ICH vs. non-ICH cohorts). The secondary end-point was difference in mortality between groups. Paired testing and uni- and multivariate regression models were applied. RESULTS: Two hundred and fifty-three patients were included, of which 54 (21%) experienced an ICH during ECMO treatment. The mortality for patients with ICH was 81% at 1 month and 85% at 6 months, respectively, compared to 28 and 33% in patients who did not develop ICH. When comparing ICH vs. non-ICH cohorts, pre-admission antithrombotic therapy (p = 0.018), high pre-cannulation Sepsis-related Organ Failure Assessment (SOFA) coagulation score (p = 0.015), low platelet count (p < 0.001), and spontaneous extracranial hemorrhage (p = 0.045) were predictors of ICH. In a multivariate regression model predicting ICH, pre-admission antithrombotic therapy and low platelet count demonstrated independent risk association. When comparing the temporal trajectories for coagulation variables in the days leading up to the detection of an ICH, plasma antithrombin significantly increased per patient over time (p = 0.014). No other temporal trajectories were found. CONCLUSIONS: ICH in adult ECMO patients is associated with a high mortality rate and independently associated with pre-admission antithrombotic therapy and low platelet count, thus highlighting important areas of potential treatment strategies to prevent ICH development.