The purpose of this study was to analyze the cost-effectiveness of lamivudine (LMV), telbivudine (LdT), and entecavir (ETV) in treatment of chronic hepatitis B with adefovir dipivoxil (ADV) resistance. Two hundred and fifty-two patients were recruited and screened for resistance to ADV and randomly assigned into three groups: LMV + ADV, LdT + ADV, and ETV + ADV. The ratio of biochemical response, virological response, seroconversion of hepatitis Be antigen (HBeAg)/hepatitis Be antibody (HBeAb), viral breakthrough, and the cost and effectiveness of treatments were analyzed. A comparison of the results of the ratio of biochemical response, virological response and seroconversion of HBeAg/HBeAb, showed no statistical difference between the three groups, with the economic cost of LMV + ADV the lowest, LdT + ADV the middle, and ETV + ADV the highest. The side effects of the three plans are all rare and tolerable. LMV + ADV is the optimal rescue strategy, and LdT + ADV the alternative selection in the economically less developed regions, while ETV + ADV was used in the economically developed regions.