Abstract: Objective To explore the variation in the gene mutation patterns and risk factors of HBV polymerase region (P) in chronic viral hepatitis (CHB) patients with nucleoside analogues therapy.Methods A total of 108 chronic hepatitis B patients with viral breakthrough after the treatment of nucleoside analogues were selected as the study subjects.The PCR product direct sequencing method was used to analyze the genetic variation of HBV P region.Results Among 108 cases,69 cases were detected by gene drug resistance,and the mutation type amount to 12,among which rtM204I was the most common (30.4％),and the second was rtL180M/rtM204I combined mutation (13％).The proportion of the major nucleoside analogues resistance highest proportion of lamivudine was 62.3％,followed by adefovir dipivoxil (21.7％) and telbivudine (15.9％).There were 33 cases with a single site mutation,29 cases with two sites mutation and 7 cases with three and above sites mutation.In the 7 cases,1 case was treated with lamivudine,1 case with entecavir,and the remaining 5 cases with irregular combined or sequential use of lamivudine,adefovir dipivoxil and entecavir.Conclusion The amino acid of HBV P gene resistant mutation is complex and varied,and rtM204V/I mutation is the most common type.Three and above sites mutation is associated with irregular combined or sequential use of lamivudine,adefovir dipivoxil and entecavir.