Patients with acute self-limited and chronic HBV infection were studied to determine their in vitro cellular immune response to HBV antigens. In interferon-gamma production cultures which were evaluated as an indicator of cellular immune response, peripheral blood mononuclear cells from patients with HBeAg-positive chronic hepatitis showed elevated response to HBcAg, while those from HBeAg-positive asymptomatic carriers revealed no response to either HBcAg or HBeAg. HBeAg-stimulated interferon-gamma production was higher in anti-HBe-positive chronic hepatitis and asymptomatic carriers than that in HBeAg-positive patients. Interferon-gamma production against HBcAg was shown to be HLA class II restricted by blocking assay using monoclonal antibodies. HBsAg with or without pre-S2 did not amplify interferon-gamma production of patients with chronic hepatitis. In acute hepatitis B, both envelope and nucleocapsid antigens induced greater interferon-gamma production than in chronic HBV carriers. These results indicate that the patients with acute hepatitis responded more to HBV antigens compared with chronic HBV carriers. Furthermore, enhanced cellular immune responses, particularly to HBeAg, were observed in anti-HBe-positive patients compared to HBeAg-positive patients during chronic HBV infection, suggesting that the poor response to HBeAg in HBeAg-positive patients may account for the failure to clear HBV.