Natural and synthetic immunomodulators that increase non-specific resistance to infection induce the production of interleukin-1 (IL-1) and tumor necrosis factor (TNF). Therefore, we investigated the effect of IL-1 and of TNF on the survival of lethally-infected mice. Mice were injected with 1 x 106 Klebsiella pneumoniae in the thigh muscle. When recombinant human IL-1 ¡3 was given as a single i.p. injection 24 h before the infection, survival was increased. Using 80 ng IL-1/? per mouse, survival compared to control animals was 80% versus 20% 48 h after the infection (p < 0.001). No effect of IL-1 was observed when it was given \ h before or 6 h after the infection. IL-1 a proved to be at least as potent as IL-1/?, Numbers of bacteria cultured from the blood, thigh muscle, liver, spleen, and kidney were similar in IL-1-treated and control animals. Protection against death by IL-1 was also investi gated in granulocytopenic mice with a Pseudomonas aeruginosa infection. Administration o f the cyclooxygenase-inhibitor, ibuprofen, did not affect the beneficial effect of IL-1. In this model human recombinant TN F was at least tenfold less active than IL-1/?. Pretreatment with IL-1 also had a significant effect on survival of mice that received a high dose of bacterial lipopolysaccharide.