Abstract: Objective To investigate whether the patients with chronic hepatitis B (CHB) could be maintained with negative HBV DNA and reduce the risk of lamivudine (LAM) resistance after the active replacement of LAM to Adefovir dipivoxil (ADV) before the occurrence of virological breakthrough.Methods Patients who had obtained virological response (i.e., the serum HBV DNA was under the lower limit of detection) and biochemical response (i.e.normalization of serum ALT) after 36 weeks of LAM monotherapy were randomly divided into group A (observation group) and group B (control group) .Patients in A group were overlapped with LAM and ADV for twelve weeks before the ADV monotherapy and patients in B group were added ADV only after the occurrence of virological breakthrough with LAM monotherapy.The virological and biochemical responses were evaluated at 48, 72, and 96 weeks during the antiviral therapy.Results The rate of negative HBV DNA was 100% (31/31) , 100% (31/31) and 96.8% (30/31) in A group, and 90.0% (27/30) , 80.0% (24/30) and 73.3% (22/30) in B group at week 48, 72, and 96.The difference was significant between week 72 and 96.The rate of normalization of liver function was 100% (31/31) , 100% (31/31) and 100% (31/31) in A group, and 93.3% (28/30) , 90.0% (27/30) and 80.0% (24/30) in B group at week 48, 72, and 96, respectively.The difference was significant at week 96 between the two groups.No severe adverse events were found in the two groups during the therapy.Conclusion Active replacement of LAM to ADV during the treatment of patients with CHB can keep the high rate of HBV DNA negative and normalization of biochemical index, and this remedy may be more suitable for patients with CHB in poor financial condition.