Either combination treatment or monotherapy using agents with a high genetic barrier are recommended for the retreatment of chronic hepatitis B (CHB) patients. In search of reasonable treatment, we compared the efficacy and safety of lamivudine (LAM) plus adefovir (ADV) and entecavir (ETV) alone for retreatment of patients with viral relapse after cessation of ADV. This is a prospective controlled study, and CHB patients with HBV DNA levels more than 4 log copies/mL were enrolled. All patients were treated with either LAM plus ADV (n=30) or ETV (n=25) for 48 weeks. After 12-months treatment, the biochemical response (BR) rates were 96.7% and 84.0%, the virological response (VR) rates were 96.7% and 68% in the LAM plus ADV and ETV groups respectively. Between two groups, the difference in BR was not significant, but in VR was statistically significant (p = 0.097 for BR, and p = 0.003 for VR). Eleven patients receiving LAM plus ADV had HBeAg seroconversion, as compared with 1 in patients receiving ETV alone (36.7% versus 4%, p = 0.003). During 12-months retreatment, 1 patients receiving ETV alone had virological breakthrough and detected ETV-resistance strains, while no LAM- or ADV-associated resistance strains were detected in patients receiving LAM plus ADV. All patients receiving LAM plus ADV were well tolerated, and no serious side effects were reported. LAM plus ADV combination therapy is effective in retreatment of CHB patients with viral relapse after cessation of ADV, but further studies are needed to obtain long term results.