The Prometheus system is a plasma filtration treatment coupling adsorption and hemodialysis (FPSA) aimed to blood purification in liver failure. After separation through an albumin-permeable membrane, plasma enters a secondary circuit where protein-bound toxic substances are removed by two adsorbers; p01, a neutral resin, and p02, an anion exchanger. Plasma is then returned to the venous line, where a high-flux hemodialyzer removes water-soluble substances. We used the Prometheus system in 12 patients with acute or acute-on-chronic liver insufficiency: eight cirrhosis, one posttransplant dysfunction, and three secondary liver insult (two cardiogenic shock and one rhabdomyolysis). All patients were severely hyperbilirubinemic, hypercholemic, and hyperammonemic. Twenty-eight sessions each lasting 340 +/- 40 minutes were performed (2.5/patient). The mean total bilirubin decreased from 33.6 +/- 20 to 22.2 +/- 13.6 mg/dL (P < .001); the reduction ratios for cholic acid and ammonia were 48.6% and 51.6%, respectively. The pre- to postsession urea reduction was 57.6% +/- 9.5% and creatinine 42.7% +/- 10%. A significant reduction was observed in the circulating levels of soluble interleukin (IL) 2 receptor (pre: 2687.2 +/- 1434.7; post: 1977.1 +/- 602 Ul/ml; P < .001) and in IL 6 (pre: 56.1 +/- 11.1; post: 35.9 +/- 10.3 pg/mL, P = .05). During treatments the hemodynamics were stable. Two patients received liver transplantations. The secondary liver insult was completely overcome in all three patients. The overall survival at 30 days was 41.6% (5/12 patients). Prometheus, based on FPSA, produced high clearance for protein-bound and water soluble markers, which resulted in high treatment efficacy.