Episodic (acute) type C hepatic encephalopathy (AHE) fails to respond to 5 days of medical therapy in 10-30% of patients and carries a 10-30% mortality rate. We prospectively studied extracorporeal liver support for AHE failing to respond to medical therapy to assess its safety and efficacy and the role of anticoagulation. A series of patients with cirrhosis and AHE failing to respond to at least 24 h of medical therapy underwent a maximum of three 6-h charcoal-based hemodiabsorption (Liver Dialysis Unit) treatments. A standard anticoagulation protocol, with heparin dosing based on activated clotting time (ACT) determinations, heparin dose-response curve, and target ACT of 275-300 s, was developed. Therapy was terminated if patients met a predetermined clinical response, deteriorated, or underwent transplantation. Eighteen patients with grade 2-4 AHE despite 5.9 +/- 3.9 days of medical therapy underwent a mean of 1.6 treatments. In 2.6 +/- 1.9 days, 16 patients (88.9%) improved to less than grade 2 HE or achieved at least a 50% hepatic encephalopathy index (HEI) reduction. Median mental status (grade 2 vs 1, p < 0.05) and HEI (0.634 +/- 0.194 vs 0.363 +/- 0.263, p < 0.005) improved significantly. Survival was 94.4% and 72.2% at 5 and 30 days, respectively. Use of our developed anticoagulation protocol resulted in less platelet (14.2% +/- 2.8% vs 32.5% +/- 5.8%, p < 0.005) and fibrinogen consumption (12.1% +/- 3.5% vs 43.3% +/- 8.6%, p < 0.0005) and blood product use (6.2 +/- 1.8 vs 19.0 +/- 5.6 units, p < 0.05) compared with treatments according to manufacturer's guidelines. Charcoal-based hemodiabsorption treatments in which a standardized anticoagulation protocol is used is safe and effective treatment for AHE not responding to standard medical therapy.