Extracorporeal albumin dialysis (ECAD) may improve severe hepatic encephalopathy (HE) in patients with advanced cirrhosis via the removal of protein or non–protein‐bound toxins. A prospective, randomized, controlled, multicenter trial of the efficacy, safety, and tolerability of ECAD using molecular adsorbent recirculating system (MARS) was conducted in such patients. Patients were randomized to ECAD and standard medical therapy (SMT) or SMT alone. ECAD was provided daily for 6 hours for 5 days or until the patient had a 2‐grade improvement in HE. HE grades (West Haven criteria) were evaluated every 12 hours using a scoring algorithm. The primary endpoint was the difference in improvement proportion of HE between the 2 groups. A total of 70 subjects [median age, 53; 56% male; 56% HE grade 3; 44% HE grade 4; median model for end‐stage liver disease (MELD) 32 (11–50) and CPT 13 (10–15)] were enrolled in 8 tertiary centers. Patients were randomized to ECAD + SMT (n = 39) or SMT alone (n = 31). Groups were matched in demographics and clinical variables. The improvement proportion of HE was higher in ECAD (mean, 34%; median, 30%) versus the SMT group (mean, 18.9%; median, 0%) (P = 0.044) and was reached faster and more frequently than in the SMT group (P = 0.045). Subjects receiving ECAD tolerated treatment well with no unexpected adverse events. Conclusion: The use of ECAD may be associated with an earlier and more frequent improvement of HE (grade 3/4). Because this 5‐day study was not designed to examine the impact of MARS on survival, a full assessment of the role of albumin dialysis awaits the results of additional controlled trials. (HEPATOLOGY 2007.)