Abstract: Antiviral treatment is the key in the treatment of chronic hepatitis B. The long- term antiviral therapy with nucleos( t) ide analogues may lead to the viral gene mutations and drug resistance,and then the sensitivity of virus to the drug is decreased. In this study,the point mutations associated with four nucleos( t) ide analogues and the incidence of mutations were investigated. The rate of drug resistance to lamivudine was highest and that of resistance to entecavir was lowest. Recent research showed that hepatitis B virus( HBV) genotype was associated with drug resistance to nucleos( t) ide analogues. In order to prevent drug resistance,the indications for antiviral therapy should be determined strictly,and then the nucleos( t) ide analogues with high efficacy and low drug resistance can be selected. And if drug resistance develops,it is necessary to add or change to another nucleos( t) ide analogue without cross resistance.