Interleukin-1 (IL-1) is radioprotective and induces both circulating colony-stimulating factor(s) (CSF) and IL-6 in mice. We evaluated the relationship among these three responses to IL-1 using anti-IL-1 receptor antibody 35F5. This antibody in vitro blocks responses of T cells and fibroblasts, but not of B cells or myeloid cell lines, to IL- 1. Administration of 35F5 alone before irradiation reduced the number of surviving mice compared with those not treated with 35F5, demonstrating that endogenous IL-1 participates in the natural resistance to radiation. Thirty micrograms of 35F5 per mouse also reduced by 92% the survival of irradiated mice pretreated with 0.3 micrograms of IL-1. Similarly, 30 micrograms of 35F5 reduced by 96% to 98% the induction of IL-6 by IL-1. In contrast, 30 micrograms of 35F5 resulted in only moderate reduction of circulating CSF. Consequently, the level of circulating CSF after 35F5 treatment was still equivalent to levels of CSF that were induced by doses of IL-1 in the radioprotective range. Because treatment with 35F5 antibody resulted in the blocking of IL-1-reduced radioprotection, the above results suggest that circulating CSF, by itself, may not be sufficient for radioprotection. This conclusion supports our previous results which showed that granulocyte-macrophage CSF (GM-CSF) and G-CSF were radioprotective only when administered with suboptimal doses of IL-1.