For hepatocytes to function effectively in a bioartificial liver device, maintained function in the milieu of plasma from patients with liver failure will be required. We have investigated the effect of plasma obtained at plasmapheresis from patients with acute liver failure on the performance of the human hepatocyte cell line HHY41 in liver-failure plasma, normal plasma, and culture medium. Cytotoxicity of plasma, DNA synthesis by thymidine incorporation, oxidative status, and cytochrome P450 functions were assayed after a 16 h culture with normal plasma, liver-failure plasma, or culture medium. Some, but not all, samples of liver-failure plasma were deleterious to the performance of the cell line, inducing cytotoxicity and oxidative stress, with diminished DNA synthesis, protein synthesis, and cytochrome P4501A activity. Strategies to minimize the toxic effects of liver-failure plasma may improve the performance of liver cells in extracorporeal liver-support devices.