Background: Plasmapheresis has been used for the treatment of acute liver failure (ALF). In these patients, hypoalbuminemia is often observed. Since albumin improves the disaggregability of erythrocytes, hypoalbuminemia might deteriorate rheology and thus influence the overall performance of plasmapheresis. Methods: Hypoalbuminemia was mimicked by using porcine blood because of its physiologically low albumin/globulin ratio (AGR). Filters (n = 16) were integrated in a closed extracorporeal in vitro system. In the control group (n = 8), native porcine blood (AGR 0.8) was used. In the study group (n = 8), we used porcine blood supplemented with human albumin to obtain the human AGR value of 1.2. Two different heparinization protocols were compared in each group (2.5 IU/ml: n = 4 with albumin and n = 4 without albumin versus 5 IU/ml: n = 4 with and n = 4 without albumin). Results: In both heparinization protocols the higher AGR led to lower transmembrane pressure (TMP) levels compared to the lower AGR. The reduced TMPs enabled higher blood flow and filtration rates. Conclusion: Maintenance of a physiological AGR in ALF patients might improve the performance of plasmapheresis and – as opposed to raised heparinization – contribute to a safer application.