The effect of human recombinant interleukin-1 receptor antagonist on intestinal inflammation, tissue destruction, and bacterial invasion during experimental shigellosis caused by Shigella flexneri was studied in the rabbit-ligated loop infection model. Intravenous infusion of the inhibitor at a dose of 2 mg/kg per h, was initiated 30 min before intestinal loops were ligated and infected, and continued during the 8-h period of infection. The animals treated with IL-1 receptor antagonist showed a striking decrease in inflammation, destruction, and bacterial invasion of their tissues, both at the level of the villous intestine and Peyer's patches. This is conclusive evidence that interleukin-1 plays a critical role in the pathogenesis of shigellosis. This proinflammatory cytokine is here proposed as a major trigger of the inflammatory reaction which is characteristic of this invasive disease of the intestine, due to the particular interaction existing between S. flexneri and macrophages.