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Backgrounds/aims: Negative hepatitis B core antigen (HBcAg) staining in hepatocytes is indicative of viral replication by an active immune response. HBcAg is expressed mainly in the cytoplasm in patients with active hepatitis and hepatocyte regeneration, and mainly in the nuclei of hepatocytes in patients with minimal liver injury in the absence of hepatocyte regeneration. The aim of this study was to elucidate whether the existence and expression pattern of HBcAg predicts the response to antiviral treatment., Methods: The study involved 58 patients with biopsy-proven chronic hepatitis B who were treated with lamivudine. Hepatitis B e antigen (HBeAg), antibody to HBeAg, hepatitis B virus DNA, and alanine aminotransferase in serum were recorded every 3 months. The inflammation grade and the fibrosis stage of chronic hepatitis were scored from 0 to 4 according to lobular inflammation, portal inflammation, periportal inflammation, and fibrosis., Results: The 58 patients included 49(84%) HBcAg-positive patients, with HBcAg staining confined to the cytoplasm in 15(31%) and in both cytoplasm and nuclei in 34(69%). The grade of lobular inflammation and the total histology score were significantly higher in patients with cytoplasmic expression of HBcAg than in HBcAg-negative patients (lobular inflammation: 2.9 vs 2.1, P=0.02; total histology score: 12.2 vs 10.3, P=0.04). The virologic responses at 3, 6, 9, and 12 months differed significantly between the cytoplasmic and mixed expression groups (P<0.01)., Conclusions: The expression pattern of HBcAg (including its possible absence) before initial therapy appears to predict the response to antiviral treatment.