For patients with acute-on-chronic liver failure (ACLF), artificial liver support system (ALSS) may help prolong lifespan and function as a bridge to liver transplantation (LT), but data on its long-term benefit are lacking. We conducted this prospective, controlled study to determine the efficacy of ALSS and the predictors of mortality in patients with hepatitis B virus (HBV)-associated ACLF.From January 2003 to December 2007, a total of 234 patients with HBV-associated ACLF not eligible for LT were enrolled in our study. They were allocated to receive either plasma exchange centered ALSS plus standard medical therapy (SMT) (ALSS group, n = 104) or SMT alone (control group, n = 130). All the patients were followed-up for at least 5 years, or until death.At 90 days, the survival rate of ALSS group was higher than that of the control group (62/104 [60%] vs 61/130 [47%], respectively; P < 0.05). Median survival was 879 days in the ALSS group (43% survival at 5 years) and 649 days in the control group (31% survival at 5 years, log-rank P < 0.05). ALSS was found to be associated with favorable outcome of these patients by both univariate and multivariate analysis. Multivariate Cox regression analysis also revealed that lower serum sodium levels, higher grades of encephalopathy, presence of cirrhosis, hepatorenal syndrome, and higher model for end-stage liver disease scores were independent predictors for both 90-day and 5-year mortality due to ACLF.Our findings suggest that ALSS is safe and may improve the short- and long-term prognosis of patients with HBV-associated ACLF.