Mice were treated with sublethal and midlethal doses of irradiation (500-700 rads) and injected intravenously with allogeneic or semiallogeneic F(1) hybrid spleen cells. The cytotoxicity developed by their spleen cells was measured with the lysis of (51)Cr-labeled target cells and was found to be stronger (although delayed in time) than the cytotoxic activity of spleen cells from nonirradiated mice. The injection of syngeneic thymus or spleen cells in the irradiated mice after their treatment with allogeneic spleen cells exerted a suppressor activity, i.e., reduced the level of cell-mediated cytotoxicity (CMC). The majority of effector cells involved in the modified CMC response of irradiated mice was shown to be of host origin and lysed specifically target cells of the same genotype as the donor. A small percentage of the cells obtained from the spleens of irradiated recipients of allogeneic spleen cells was composed of donor cells which lysed specifically target cells of the same genotype as the host. These results demonstrate that the precursors of the cytotoxic cells responsible for target cell lysis are relatively radioresistant and suggest that their response is regulated by radiosensitive thymus-dependent cells.