In chronic hepatitis B virus (HBV) infection, immune responses to hepatitis B core antigen (HBcAg) are weak. Interleukin (IL)-10 is a potent immunosuppressive cytokine which we reported recently to be secreted in response to HBcAg by peripheral blood mononuclear cells (PBMCs) from patients with chronic HBV infection or healthy controls. Using an enzyme-linked immunospot assay, we compared the ability of HBcAg to stimulate IL-10 production by PBMC with that of lipopolysaccharide (LPS), phytohaemagglutinin-P and hepatitis C virus-derived antigens in 16 patients with chronic HBV infection and six healthy controls. Frequencies of IL-10 spot-forming cells (SFC) in response to HBcAg were comparable to those obtained with LPS in patients with chronic HBV infection. Frequencies of IL-10 SFC in response to HBcAg or to LPS were significantly higher in patients with chronic HBV infection than in healthy controls. IL-10 SFC in response to HBcAg consisted of 26–35% T cells, 62–70% monocytes and less than 1% B cells in patients with chronic HBV infection. Only monocytes contributed to IL-10 production in controls. Frequencies of HBcAg stimulated IL-10 SFC representing T cells and monocytes were significantly higher in patients with elevated serum alanine aminotransferase (ALT) and detectable HBV DNA than in patients with normal ALT and undetectable HBV DNA. The potent ability of HBcAg to stimulate IL-10 production by PBMC may contribute importantly to immune tolerance toward HBV.