SUMMARY.Recombinant hepatitis C virus (HCV) core protein from aal‐164, designated cpl‐10, was used to immunize mice. Antibodies to cpl‐10 were produced in all seven strains of congenic mice; none of the strains could be considered low responders relative to the others. The mouse response against individual epitopes of HCV core protein varied from one strain to another: B1O.RIII (H‐2r) recognized all three peptides aa13–30, aa77–90, aa129–145; B10.D2 (H‐2d), B10 (H‐2b) and C3M.SW (H‐2b) responded to aa13–30, aa77–90; B10, M (H‐2f), B1O.BR (H‐2k) and C3H/HeJ (H‐2k) reacted with aa13–30 only. Competitive inhibition of binding demonstrated that antibody to the peptide was inhibited by cpl‐10 protein and the corresponding peptide only. Recombinant HCV core protein is highly immunogenic and can elicit good antibody response in mice. The aa13–30 is a major epitope of HCV core protein in mice. The humoral response to the distinct epitopes was regulated by the H‐2 genes. Further analysis indicated that the I‐a locus of H‐2 genes determined the antibody response to aa13–30 and 77–90. These results suggest that the variation of antibody responses to HCV in humans may partially cont