Extracorporeal devices have had limited effectiveness in liver failure due to consequences of inadequate anticoagulation. The purpose of this study was to evaluate an anticoagulation protocol developed for Liver Dialysis Unit (LDU) treatments. Twelve patients underwent 19 LDU treatments for acetaminophen overdose (n = 1), subacute liver failure (n = 1), and refractory encephalopathy in cirrhosis (n = 10). The initial 6 patients (group 1) were treated according to the manufacturer's recommendations. The subsequent 6 patients (group 2) were treated using a formal heparin anticoagulation protocol that included 2000 units in prime solution and 30 units/kg induction, activated clotting time (ACT) measurements, and heparin administered by dose-response curve to maintain 300-second ACT. Protamine reversal was used. Treatments were well tolerated and equally effective in both groups. Adequate (ACT > or = 250 seconds) and therapeutic (ACT 250-350 seconds) anticoagulation was maintained more consistently in group 2 (90.9% vs 50.0%, p < 0.0001; and 77.4% vs 45.8%, p < 0.001). There was less consumption of fibrinogen (12.1% vs 43.3%, p < 0.005) and platelets (13.8% vs 29.9%, p < 0.05) and a trend for less blood product used (8.3 vs 15.8 units/patient, p = 0.13) and fewer complications (16.7% vs 66.7%, p = 0.15) in group 2. Anticoagulation using ACT monitoring, heparin dose-response curves, and a target ACT of 300 seconds improves the safety of LDU treatments.