Current therapeutic approaches to control chronic hepatitis B (CH-B), such as administrations of interferon or nucleoside analogs, are still unsatisfactory. Vaccination with conventional hepatitis B (HB) vaccine is another therapeutic approach with lower cost and potentially long-lasting beneficial effect. However, a response rate to vaccination therapy is not necessarily high. Therefore, combination therapy of interferon, nucleoside analogs and vaccination, would be the promising therapeutic approach that improves therapeutic effect and solves the problems of individual therapies. Herein, we report the results of the clinical trial, the combination therapy of lamivudine (LAM) and HB vaccine in patientswith B-CH as one of the candidates for the combination therapies. The results indicate that the combination therapy of LAM and HB vaccine was more effective in regulating viral replication than the LAM monotherapy was. In addition, no adverse effect was observed in the patients given HB vaccine. This novel therapy should be further examined for the improvement of its efficacy and achievement of continuous suppression of HB virus replication.