Cytokines that stimulate growth and differentiation of hematopoietic precursor cells have been used as protectors in vivo against ionizing radiation. Recently, we have shown that the nitroxide tempol is also an effective radiation protector in vivo. The purpose of the present study was to determine if the combination of tempol with stem cell factor (SCF, c-kit ligand) would provide enhanced radiation protection in C57 mice compared with the protection afforded by either agent alone. Mice were exposed to whole-body irradiation and assessed for survival at 30 days after irradiation. No control mice survived doses of more than 9 Gy. Treatment of mice before and after radiation with SCF alone (100 micrograms/kg at -20 h, -4 h and +4 h) protected mice from radiation at doses of as high as 10 Gy (76% survival). Tempol (350 mg/kg) given 10 min prior to radiation was a radioprotector at 9 Gy (55% survival). The combination of SCF and tempol increased the survival of mice exposed to radiation doses up to 11 Gy (32% survival for the combination vs 4% for SCF alone and 0% for tempol alone; P < 0.001 for the combination vs either agent alone). Lower doses of SCF alone (1 microgram/kg) or tempol alone (275 mg/kg) did not protect mice from radiation. However, the combination of these reduced doses of SCF and tempol protected mice from lethal irradiation at 10 Gy. Stem cell factor and tempol given either singly or together were well tolerated by the animals. These data show that SCF and tempol are radiation protectors and that their radioprotective effects are more than additive when the agents are given together.