NF-kappa B comprises a family of cellular transcription factors that are involved in the inducible expression of a variety of cellular genes that regulate the inflammatory response(1,2). NF-kappa B is sequestered in the cytoplasm by inhibitory proteins, I kappa B, which are phosphorylated by a cellular kinase complex known as IKK. IKK is made up of two kinases, IKK-alpha and IKK-beta, which phosphorylate I kappa B, leading to its degradation and translocation of NF-kappa B to the nucleus(3-9). IKK kinase activity is stimulated when cells are exposed to the cytokine TNF-cu or by overexpression of the cellular kinases MEKK1 and NIK10,11. Here we demonstrate that the anti-inflammatory agents aspirin and sodium salicylate specifically inhibit IKK-beta activity in vitro and in vivo. The mechanism of aspirin and sodium salicylate inhibition is due to binding of these agents to IKK-beta to reduce ATP binding. Our results indicate that the anti-inflammatory properties of aspirin and salicylate are mediated in part by their specific inhibition of IKK-beta, thereby preventing activation by NF-kappa B of genes involved in the pathogenesis of the inflammatory response.