Administration of IL-12 prior to lethal irradiation, protected a significant fraction of mice from 60Co-gamma radiation-induced lethal hematopoietic syndrome. Radioprotection was associated with an increase in the number of c-kit+ bone marrow cells (BMC) in IL-12 treated mice compared to saline-treated mice. Even after supralethal doses of radiation (1200 cGy), IL-12-treated mice had twofold greater numbers of c-kit+ BMC than controls. However the mice receiving IL-12 and 1200 cGy died of the gastrointestinal (GI) syndrome, evident by gross necroscopy and histological evaluation, within 4 to 6 days after irradiation. Induction of the GI syndrome in mice not treated with IL-12 required radiation doses of 1600 cGy. Thus, at doses of radiation at which IL-12 still protects c-kit+ hematopoietic cells, it sensitizes the intestinal tract to damage. Radioprotection with IL-12 was abrogated by anti-IL-1R or anti-SCF antibody, but not anti-IFN gamma antibody. In contrast, anti-IFN gamma antibody abrogated sensitization of the intestinal tract by IL-12.