Survival after irradiation with LD100/30 (radiation dose lethal to 100% of mice in 30 days) is based on recovery of impaired hematopoietic function. Our previous studies using antibodies to interleukin-1 receptor (IL–1R), tumor necrosis factor (TNF), and IL–6 demonstrated that endogenous production of these three cytokines is required for untreated mice as well as mice protected with lipopolysaccharide (LPS), IL–1, or TNF to survive lethal irradiation. In this report we show that anti-c-kit ligand/steel factor (SIF) antibody similarly abrogates LPS- and IL-1-induced radioprotection. Furthermore, administration of this antibody to unmanipulated mice increased LD50/30 radiation lethality from 50% to 100%. Such an effect was not obtained using anti-IL-3, anti- IL–4, or anti-granulocyte-macrophage colony-stimulating factor antibody. Thus, like IL–1, TNF, and IL–6, SIF is required for survival from lethal irradiation.