Objective To investigate the relationship between HBV mutations in the precore (PC)/core promoter region and the liver histological changes in HBeAg negative CHB patients. Method A total of 71 HBeAg negative CHB patients with liver biopsy from April 2012 to Dec 2013 were enrolled. DNA was extracted from blood serum, then the HBV S gene and PC/core promoter region were amplified by semi-nested PCR and sequenced. The relationship between significant liver histological changes and viral factors were analyzed by Logistic regression analysis. Results The incidence of significant necroinflammation (15.8% vs. 27.3%, χ2 =1.398, P = 0.237) and significant fibrosis (71.1% vs. 84.4%, χ2= 1.926, P = 0.165) were found to be similar between patients infected with HBV genotype B and genotype C . By Logistic regression analysis including risk factors of age, sex, HBV genotype and mutations (T1753V,A1762T/G1764A,A1846T and G1896A), the A1762T/G1764A mutation in HBV associated with significant necroinflammation (OR = 4.296, P = 0.037), while factors of age, sex, genotype and other mutation were not associated with significant liver histological changes. (all P > 0.05). Conclusion Mutation in PC/core promoter region of HBV may act as a marker to evaluate the liver histological changes.