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Background: Bleeding events are frequent complications during extracorporeal membrane oxygenation therapy (ECMO). Objective: To determine the rate of acquired factor XIII deficiency and its association with major bleeding events and transfusion requirements in adults undergoing ECMO therapy. Materials and Methods: A retrospective single centre cohort study. Adult patients receiving veno-venous or veno-arterial ECMO therapy during a 2-year period were analysed and screened for factor XIII activity measurements. Factor XIII deficiency was defined based on the lowest factor XIII activity measured during ECMO therapy. Results: Among 84 subjects included into the analysis, factor XIII deficiency occurred in 69% during ECMO therapy. There were more major bleeding events (OR, 3.37; 95% CI, 1.16–10.56; p = 0.02) and higher transfusion requirements (red blood cells, 20 vs. 12, p < 0.001; platelets, 4 vs. 2, p = 0.006) in patients with factor XIII deficiency compared to patients with normal factor XIII activity. In a multivariate regression model, factor XIII deficiency was independently associated with bleeding severity (p = 0.03). Conclusions: In this retrospective single centre study, acquired factor XIII deficiency was observed in 69% of adult ECMO patients with a high bleeding risk. Factor XIII deficiency was associated with higher rates of major bleeding events and transfusion requirements. [ABSTRACT FROM AUTHOR]