Current methods for identification of oxygenator clotting during prolonged extracorporeal life support include visual inspection, evaluation of oxygenator resistance and oxygen exchange performance, and assessment of clotting-related laboratory parameters. However, these observations do not provide a quantitative assessment of oxygenator clot formation. By measuring changes in the dynamic oxygenator blood volume this study aimed to evaluate the relation to oxygenator resistance and oxygen transfer performance. Sixty-seven oxygenators were studied during adult extracorporeal life support. Oxygenator blood volume, oxygenator resistance, and oxygen transfer efficiency were monitored. Oxygenator blood volume decreased with increasing runtime (r = -0.462; p <0.001). There was a statistically significant, fair negative correlation between oxygenator blood volume and oxygenator resistance (r = -0.476; p<0.001) in all oxygenators, which became stronger analyzing only exchanged oxygenators (r = -0.680; p<0.001) and oxygenators with an oxygenator blood volume <187 mL (r = 0.831; p<0.001). No relevant correlation between oxygenator blood volume and O₂ transfer was found. Oxygenator blood volume declined over time and was clearly associated with an increasing oxygenator resistance during prolonged extracorporeal life support, though O₂ transfer was less affected.