Hepatitis B virus (HBV) core antigen (HBcAg)-specific CD4⁺ T-cell responses are believed to play an important role in the control of human HBV infection. In the present study, HBcAg-specific, HLA-DR13*-restricted CD4⁺ Th1-type T-cell clones were generated which secreted both gamma interferon and tumor necrosis factor alpha after in vitro antigen stimulation. These HBcAg-specific CD4⁺ Th1-type T cells were able to lyse HBc peptide-loaded Epstein-Barr virus-transformed lymphoblastoid target cells in vitro. To examine whether these HLA-DR13*-restricted human CD4⁺ Th1 T cells also display the same cytotoxic effects in vivo, we transferred peripheral blood leukocytes (PBL) derived from HBV-infected donors or an HBV-naïve donor sharing the DR13*, together with the HBcAg-specific CD4⁺ Th1-type T cells and HBcAg, directly into the spleen of optimally conditioned Nod/LtSz-Prkdc^scid/Prkdc^scid (NOD/SCID) mice. The production of both secondary anti-HBc-immunoglobulin G (anti-HBc-IgG) and primary HBcAg-binding IgM in hu-PBL-NOD/SCID mice was drastically inhibited by HBcAg-specific CD4⁺ Th1-type T cells. No inhibition was observed when CD4⁺ Th1 cells and donor PBL did not share an HLA-DR13. These results suggest that HBcAg-specific CD4⁺ Th1 T cells may be able to lyse HBcAg-binding, or -specific, B cells that have taken up and presented HBcAg in a class II-restricted manner. Thus, HBcAg-specific CD4⁺ Th1-type T cells can modulate the function and exert a regulatory role in deleting HBcAg-binding, or -specific, human B cells in vivo, which may be of importance in controlling the infection.