The role of infection with hepatitis B virus (HBV) genotypes on liver histology is largely unknown. The aim of study was to investigate the relationships between HBV genotypes (B, C), core-promoter (CP) and precore mutants and liver histology in 66 patients. Liver biopsies were scored by histologic activity index (HAI). HBV genotypes were determined by enzyme-linked immunosorbent assay (ELISA). Eighteen (27.3%) and 48 patients (72.7%) had genotype B (all were subtype Ba) and C, respectively. Forty-seven (71.2%) and 27 (40.9%) had CP and precore mutations, respectively. Patients with genotype C compared with subtype Ba had higher median scores of HAI-necroinflammation (HAI-NI) (7 vs 3), HAI-fibrosis (HAI-F) (1 vs 0) and total HAI (8.5 vs 3) (all P < 0.03). Patients with CP mutations compared with wild-type had higher median scores of HAI-NI (7 vs 3), HAI-F (3 vs 0) and total HAI (9 vs 3) (all P < 0.03). Forty patients (83.5%) with genotype C had CP mutations. Age and alanine aminotransferase levels were positively correlated with HAI scores while albumin levels were negatively correlated (P < 0.01 for all, except albumin levels and HAI-F, P = 0.08). There was no association between precore mutations and HAI scores. Multivariate analysis indicated that higher alanine aminotransferase (ALT) levels were associated with higher HAI scores (P < 0.04) and CP mutations were associated with higher HAI-NI (P = 0.034), but not with HAI-F score (P = 0.3). CP mutations were associated with more severe necroinflammation. The association between genotype C and poor histology was probably because of the association between genotype C and CP mutations.