Jian-Hong Zhong,1,* Yang Ke,1,2,* Shao-Liang Zhu,1,* Lin Wang,2 Cheng-Piao Luo,3 Wen-Feng Gong,1 Xue-Mei You,1 Liang Ma,1 Bang-De Xiang,1 Le-Qun Li1 1Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, 2Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, 3Department of Pathology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, People’s Republic of China *These authors contributed equally to this work Aim: Lamivudine (LAM) and adefovir dipivoxil (ADV) are widely used in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), but few studies have directly compared their therapeutic efficacy and treatment cost. This study aims to compare LAM with ADV head-to-head in these patients. Methods: We retrospectively analyzed 201 patients with HBV-related HCC who underwent radical resection and subsequently received LAM (n=155) or ADV (n=46). The two groups were compared in terms of HBV-DNA levels, liver function, antiviral resistance, recurrence-free, and overall survival, as well as antiviral medication costs. Results: Despite significant improvement in HBV-DNA and alanine aminotransferase level in the LAM group after 1 year of antiviral therapy, these parameters did not differ significantly between the two groups over the following 2 years. Incidence of antiviral resistance after 1, 2, and 3 years of antiviral treatment was significantly higher in the LAM group (19.5%, 45.7%, and 56.4%) than in the ADV group (0%, 3.3%, and 14.5%; P