Pretreatment with recombinant interleukin 1 (IL 1) protects mice in a dose-dependent manner from lethal effects of ionizing radiation. Two thousand units of IL 1, given i.p. 20 hr before irradiation, protect 88% of C57B1/6 mice from an LD100/17 radiation dose (dose of radiation that kills 100% mice in 17 days), and 1000 U of IL 1 protect 100% of DBA/1 mice from an LD50/30 dose. This finding provides the first evidence that a cytokine, IL 1, which acts as a differentiation- and maturation-inducing agent for a variety of cells, also can serve as a signal that initiates radioprotective events in vivo. Because many of the exogenous immunomodulators that have been shown to be radioprotective also induce endogenous IL 1 production, our observation suggests that IL 1 may mediate their radioprotective effects.