Interleukin-1 (IL-1) is an important mediator of inflammatory disease. The IL-1 family currently consists of two agonists, IL-1 alpha and IL-1 beta, and one antagonist, IL-1ra. Each of these molecules binds to the type I IL-1 receptor (IL1R)(1). The binding of IL-1 alpha or IL-1 beta to IL1R is an early step in IL-1 signal transduction and blocking this interaction may therefore be a useful target for the development of new drugs, Here we report the three-dimensional structure of IL-1 beta bound to the extracellular domain of IL1R (s-IL1R) at 2.5 Angstrom resolution. IL-1 beta binds to s-IL1R with a 1:1 stoichiometry. The crystal structure shows that s-IL1R consists of three immunoglobulin-like domains which wrap around IL-1 beta in a manner distinct from the structures of previously described cytokine-receptor complexes. The two receptor-binding regions on IL-1 beta identified by site-directed mutagenesis(2,3) both contact the receptor : one binds to the first two domains of the receptor, while the other binds exclusively to the third domain.