Two“natural resistance”functions, natural killer (NK) cell activity against YAC-1 lymphoma cells and rejection by irradiated mice of parental-strain or H-2 allogeneic bone marrow cell grafts (hybrid or allogeneic resistance) were compared in mice at ages between 10 weeks and 26 months. NK cell numbers, as assessed by target-binding cells, decreased to one-half that of young mouse spleen cells, whereas NK lytic function was much more depressed. Hybrid, but not allogeneic, resistance to marrow grafts was weakened by 17 months of age. The immunogenicity of marrow stem cells of old Fl hybrid mice had not changed. The interferon inducer polyinosinic:polycytidylic acid (pI:pC) restored hybrid resistance to marrow grafts but only weakly boosted NK cell function in old mice. Incubation of spleen cells of old mice withβinterferon resulted in a weak boosting ofNK cell activity. No cells capable of inhibiting NK cell function were detected in the spleens of old mice. These findings in old mice were similar to findings in young mice treated with89Sr, with the exceptions that both hybrid and allogeneic resistance to marrow grafts are defective in89Sr-treated mice and pT.pC failed to restore hybrid resistance in mice treated with89Sr. This loss of“natural resistance”by aged mice, perhaps mediated by marrow-dependent effector cells, can partially explain the increased incidence of tumors in aging populations.