Abstract: Objective To evaluate the long-term efficacy of different treatment protocol of Adefovir dipivoxil in chronic hepatitis B patients with Lamivudine-resistance.Methods 63 chronic hepatitis B patients with Lamivudine-resistance and compensated liver function were enrolled and were randomly divided into group A and group B.In group A, indefinite Lamivudine in combination with Adefovir dipivoxil was given, and the treatment was continued in patients with reduced serum HBV DNA level greater than 2 log10 or the serum HBV DNA being below the detectable level for 6 months.In group B, lamivudine was given in combination with Adefovir dipivoxil in the first 3-6 months, then the monotherapy of Adefovir dipivoxil was continue in the cases with reduced serum HBV DNA level greater than 2 log10 or the serum HBV DNA becoming undetected.In all the patient, the liver function test was performed periodically, the serum HBV DNA was detected every 3 months, Lamivudine resistance mutations (rtA173T/V and rtL180M) and Adefovir dipivoxil resistance mutations (rtA181T/V and tN236T) were tested every 6 months.Results Group A is superior to group B in preventing further drug-resistance of hepatitis B virus and the following virological and biochemical breakthrough.Conclusion Therapy of indefinite Lamivudine in combination with Adefovir dipivoxil can prevent further drug-resistance of hepatitis B virus and the following virological and biochemical breakthrough.