The leukocyte integrin Mac-1 (αMβ2, CD11b/CD18) regulates important cell functions in inflammation, including adhesion, phagocytosis, and oxidative burst. Deficiency of Mac-1 reduces vessel wall inflammation and neointimal thickening after murine carotid artery injury. Although Mac-1 has been implicated in modulating AP-1 and NF-κB activity, the signal transduction pathways involved are undefined. cDNA array analysis of Mac-1–clustered compared with –nonclustered monocytic THP-1 cells showed increased expression of the signal transducer TRAF6 (TNF receptor–associated factor 6), leading us to consider the possibility that Mac-1 used a Toll/IL-1 receptor family–like signaling pathway. Mac-1–dependent activation of NF-κB was potentiated by wild-type, and attenuated by dominant negative, TRAF6- and TGF-β–activated kinase (TAK1) constructs. IRAK1 (IL-1 receptor associated kinase), a kinase immediately upstream of TRAF6, coimmunoprecipitated with Mac-1. Taken together, these observations indicate that Mac-1 recruits a Toll/IL-1 receptor family–like cascade to modulate NF-κB activity. This represents a new pathway for integrin-dependent modulation of gene expression.