Objective To investigate the mutations of basal core promoter (BCP) and precore (PreC) region of hepatitis B virus (HBV) and the association with the development of hepatocellular carcinoma in patients with chronic HBV infection.Methods Totally 381 untreated HBV patients were recruited from the Department of Infectious Diseases,People's Hospital of Shangyu from Jan 2003 to Dec 2010,which included patients with chronic hepatitis B (CHB,n =166),cirrhotic hepatocellular carcinoma (cirrhotic-HCC,n =158) and noncirrhotic hepatocellular carcinoma (noncirrhotic-HCC,n=57).The mutations in HBV BCP and PreC and the genotypes of HBV were determined by polymerase chain reaction (PCR) and direct sequencing.Data were analyzed by chi square test and Logistic regression.Results The HBV genotype of most cases was genotype B (CHB,n =124;cirrhotic-HCC,n=126 ; noncirrhotic-HCC,n=50).In univariant analysis,BCP V1753 (x2 =7.927,P=0.005),BCP T1762/A1764 (x2 =12.796,P＜0.01),PreC A1896 (x2 =6.890,P=0.009) and PreC A1899 (x2=11.850,P =0.001) mutations were more frequently detected in cirrhotic-HCC patients than those in CHB patients.PreC A1896 (x2 =27.310,P＜0.01) and A1899 (x2=7.575,P=0.006) mutations were highly detected in noncirrhotic-HCC patients than those in CHB patients.Multivariate Logistic regression analysis revealed that in HBeAg positive patients,BCP T1762/A1764 (wald=6.180,P=0.016,OR=8.883) and PreC A1899 (wald=10.279,P=0.001,OR=7.475) mutations were independently associated with the development of cirrhotic-HCC; PreC A1896 (wald=4.324,P=0.038,OR=4.439) and PreC A1899 (wald=4.850,P=0.028,OR=6.010)mutations were independently associated with the development of noncirrhotic-HCC.While in HBeAg negative patients,PreC A1896 mutation (wald=15.448,P＜0.01,OR=12.128) was independently associated with the development of noncirrhotic-HCC.Conclusions BCP T1762/A1764 mutations are associated with the development of cirrhotic-HCC in HBeAg positive patients.PreC A1896 mutation is associated with the development of noncirrhotic-HCC in HBeAg positive and HBeAg negative patients.PreC A1899 mutation is associated with the development of cirrhotic-HCC and noncirrhotic-HCC in HBeAg positive patients.