Objective: To investigate the clinical efficacy of the combination of entecavir and interventional therapy in treatment of hepatitis B virus (HBV)-related hepatocellular carcinoma (HBVR-HCC). Methods: From February 2007 to February 2011, 85 patients definitely diagnosed as HBVR-HCC and without indication for surgery were selected. Of the patients, 44 cases underwent entecavir plus transarterial chemoembolization (TACE) treatment (observational group), and 41 cases received TACE alone (control group). The HBV DNA level, liver function, AFP level, and Child-Pugh score of the two groups before treatment and at 4, 12, 24, and 48 weeks after treatment were analyzed, and the clinical efficacy, incidence of adverse effects, and survival status between the two groups were compared. Results: With prolongation of treatment time, the HBV-DNA level in observational group was gradually decreased, while in control group it was gradually increased, and the differences at each time point after treatment between the two groups had statistical significance (P<0.05); the alanine transaminase (ALT) and AFP levels were gradually decreased, but their decreasing degrees were greater than those in control group after 24-week treatment (all P<0.05); the Child-Pugh scores in both groups were gradually increased but the increasing degree in observational group was significantly lower than that in control group after 24-week treatment (P<0.05). The effective rate of treatment in observational group was significantly higher, while the incidence of complications and adverse reactions in observational group was significantly lower than those in control group (all P<0.05). No statistical difference was noted in 1-year survival rate between the two groups (P>0.05), but the 2-year survival rate and median survival time in observational group were better than those in control group (both P<0.05). Conclusion: TACE may motivate the activity of HBV replication, and the combination of antiviral and TACE treatment for HBVR-HCC can effectively control HBV replication, and improve liver function without increase of side effects.