To analyse the immune response to the hepatitis C virus (HCV) core protein, we immunized mice with the protein. BALB/c (H-2d) and C3H/He (H-2k) mice were high responders, while C57BL/6 (H-2b) mice were low responders in terms of Th cell proliferative responses. All the strains showed comparable levels of antibody responses to the HCV core protein. The Th cell lines recognized residues 61-90 of the HCV core protein in the context of I-Ad (BALB/c) and residues 11-30 in the context of I-Ek (C3H/He), respectively. The Th cell lines were restricted by I-Ab in C57BL/6 mice but recognized no synthetic peptide that spanned the region, although derivative clones from the line recognized residues 1-20 and 91-110 of the HCV core protein, respectively. The Th cell lines were Th 1 subset in all three strains based on the profile of lymphokine secretion. The major B cell epitope of the protein was found to be within residues 21-40 of the HCV core protein in all three strains. These observations should be useful for better understanding of the immune response to the HCV core protein in vivo.