Objective To evaluate the therapeutic efficacy of combination therapy comprised of plasma perfusion (PP) , and plasma exchange (PE) , and entecavir for treating patients with hepatitis B virus (HBV) -related acute-on-chronic liver failure (ACLF) .Methods Seventy-six patients with HBV-ACLF were divided into two equal treatment groups: control, receiving the basic treatment of PE (time: 1.5-2.5 h, blood flow rate: 110-150 ml/min, plasma separation rate: 20-30 ml/min, replacement plasma volume: 2200-2800 ml) and entecavir (0.5 mg/d) for four weeks;combination therapy, receiving the basic treatment plus PP absorption.Serum levels of total bilirubin (TBil) , prothrombin activity (PTA) , and albumin (Alb) were measured before treatment, at the end of treatment, and at 72 h post-treatment.Results The total effective rate of the combination therapy group was significantly higher than that of the control group (62.9% vs.61.8%, P>0.05) .Serum TBil levels at the end of treatment and at 72 h post-treatment were significantly lower than those before treatment for both groups (P<0.05) , but the decrease in levels was significantly more extensive in the combination therapy group than in the control group (P<0.05) .Levels of PTA and Alb in the control groups were significantly higher at the end of treatment than before treatment (P<0.05) , and the levels were even more extensively decreased at 72 h post-treatment (P<0.05) .Compared with the pre-therapy levels, serum PTA and Alb in the combination therapy group were not different at the end of treatment or at 72 h post-treatment.Conclusion Adding PP to the basic therapy of PE and entecavir increases the efficacy for treating HBV-ACLF.