During acute liver failure, hybrid liver support therapy could serve as a bridge to liver transplantation. In this desired temporary use, immune competent cell responses, such as the production of cytokines, might be of limiting relevance. We have investigated the Tumor Necrosis Factor-alpha (TNF) liberation in two models using pigs, connected with an extracorporeal bioreactor with homologous hepatocytes: TNF liberation was measured in arterial plasma during a 4 day perfusion time in untreated animals, model (i), and during short term perfusion of hepatectomized pigs in model (ii). Animals four days after catheter implantation in model (i) had TNF values of < 5 pg/ml. After connecting the system without hepatocytes, TNF rose to 9.7 +/- 2 within 120 min and rose further to 32.6 +/- 6 pg/ml within 4 hours after filling the system with the homologous hepatocytes. After 24 hours of continuous perfusion and during four days of perfusion, the TNF levels were lowered to baseline levels. In model (ii), TNF rose to 220 +/- 130 pg/ml within 180 min and decreased to 110 +/- 10 pg/ml within six hours, whereas controls without hepatocytes showed mean levels with a maximum of 120 +/- 20 pg/ml. In both models, there was no correlation between TNF levels and clinical abnormalities such as fever or shock symptoms. There is evidence for an activation of blood cells during experimental extracorporeal hybrid support. No typical side effects were, however, observed. Thus, TNF mediated extracorporeal cell activation does not appear to limit the application of homologous hybrid liver support therapy.