Over the past decade, increasing attention has been focused on the contribution of naturally occurring mutations in the hepatitis B virus (HBV) genome to the clinical course of the chronic infection. The aim of this study was to investigate the effect of the HBV pre-core mutation G1896A on the expression of HLA class II molecules and the core protein of hepatitis B in liver biopsies of chronic hepatitis B (CHB) infection. In 30 HBeAg-negative CHB patients the pre-core region of the HBV genome was amplified and sequenced to determine the presence of the mutation G1896A. Liver biopsies were scored based on the Histology Activity Index (HAI) system and immunohistochemistry (IHC) was performed to study the expression of HLA class II molecules on the antigen-presenting cells and the core protein in hepatocytes. We found that 19 of the 30 patients (63%) harbored the G1896A mutation. Compared to the patients without this mutation, those with G1896A had lower HAI scores (5.0 +/- 2.8 versus 7.9 +/- 4, p = 0.03). The study of the expression of HLA-II molecules in our patients revealed that subjects with the G1896A mutation had lower expression of HLA-II compared to wild-type infected subjects (1.87 +/- 0.6 versus 3.27 +/- 1.5, p < 0.01). Core protein expression was present in four patients (13.3%) who had higher HBV DNA levels than patients without core protein expression (3.81 +/- 0.78 versus 2.02 +/- 0.16, p < 0.001). These results suggest that the G1896A pre-core mutation may directly interfere with antigen presentation, most likely by decreasing the availability of HLA class II molecules, and this may result in less aggressive liver disease in HBeAg-negative CHB infection.