Antigenic differences between lymphocytes from young and old female C57BL/6 mice were studied using 3 techniques. In one-way mixed lymphocyte reactions significant responses were obtained in 7.7% of the young → young combinations, 13.5% of the young → old, 18.2% of the old → young and 23.7% of the old → old. Polyethylene glycol enhanced the weak syngeneic MLR responses in all groups. Young anti-old antiserum was raised in young animals by injecting with lymphoid cells from old mice. The serum was cytotoxic to spleen cells from 5 of 6 old mice aged in animal facilities at University of Alabama in Birmingham and from 2 of 12 mice aged at Charles River. Lymphocytes from young mice were sensitized to old lymphocytes in a mixed lymphocyte culture and their cytotoxicity toward old cells measured in a chromium-release assay. No cytotoxicity was observed with sensitized lymphocytes from 5 young mice under various conditions. These results do not support the hypothesis that altered antigenic determinants are always or even usually present on the lymphocytes of old mice. © 1983.