SUMMARY High (Ab/H) and low (Ab/L) responder lines of mice have been separated by selective breeding for their ability to synthesize humoral antibodies against many unrelated antigens. By contrast, no interline difference has been found so far in cell-mediated immunity. In the present article, the immune responsiveness of the two lines against histocompatibility antigens is studied. Interline skin grafts were rejected in 10.4 days by Ab/L mice and in 12.6 days by Ab/H mice. This difference is significant P<0.01. The survival of intraline skin grafts was more prolonged and showed a wide range of rejection times. Cytotoxic antibody production was markedly higher in Ab/H than in Ab/L mice after immunization with spleen cells or following rejection of first- or second-set skin grafts. A clear-cut interline separation between the humoral and cellular immune responses against histocompatibility antigens has therefore been produced by the selective breeding.