Background: There has been little information on the antiviral efficacy and safety of lamivudine and entecavir in hepatitis B virus (HBV)-related advanced hepatocellular carcinoma (HCC). Thus, we compared the efficacy and safety of lamivudine versus entecavir in patients with advanced HCC who have relatively short survival rate. Methods: We reviewed the medical records of 134 nucleotide analogue-na?ve patients with chronic hepatitis B (CHB) who were diagnosed as having advanced HCC (TNM stage III-IV) between January 2005 and September 2009. Of these, 87 (64.9%) and 47 (35.1%) patients received lamivudine (LAM group) and entecavir (ETV group), respectively, after HCC diagnosis. Results: The mean age of the patients (115 men and 19 women) was 53 years. The median HBV DNA and alanine aminotransferase level was 6.30 (range, 4.72-8.72) log10copies/mL and 61.50 (range, 11.00-809.00) IU/L, respectively. Most patients (n=98, 73.1%) had Child-Pugh class A liver function whereas the other 36 (26.9%) had Child-Pugh B. Sixty five (48.5%) and 69 (51.5%) patients had HCC with TNM stage III and IV, respectively. Treatment outcomes during follow-up period including virologic, biochemical and serologic response (HBeAg loss/seroconversion) and appearance of antiviral resistance were similar between LAM and ETV groups. On multivariate analysis, Child-Pugh class, alpha-fetoprotein, and TNM stage were identified as independent predictors of overall survival (all p<0.05). However, the use of lamivudine or entecavir did not influence overall survival. The overall survival of LAM and ETV group was similar (median 9.60 vs. 13.60 months; log-rank test, p=0.493). In both groups, HBV flare up and interruption of HCC treatment due to hepatic dysfunction was not noted. Conclusions: The treatment outcome of lamivudine and entecavir was similar and antiviral treatment did not influence overall survival in patients with advanced HCC. Thus, lamivudine which is less expensive than entecavir might be sufficient to control HBV in patients with advanced HCC.