Activation of Toll-like receptor (TLR)-dependent signaling leads to the expression of genes encoding proinflammatory factors, such as tumor necrosis factor-α (TNF-α), and this proinflammatory gene expression is sustained for the duration of the inflammatory response. TLR4-mediated inflammation, which occurs in two phases, depends on the TNF family member 4-1BB ligand (4-1BBL) to sustain TNF-α production during late-phase signaling. We showed that Toll-interleukin-1 receptor (TIR) domain-containing adaptor protein (TIRAP) and the kinase IRAK2 interacted with 4-1BBL to mediate late-phase TLR4 signaling. Expression of 4-1bbl depended on early TLR4 signaling that also induced Tnf expression, and 4-1BBL translocated to the plasma membrane, where it interacted with TLR4 to mediate late-phase signaling. TLR4-4-1BBL-mediated signaling depended on TIRAP and IRAK2, as well as a complex consisting of the E3 ubiquitin ligase TRAF6 (TNF receptor-associated factor 6), the kinase TAK1 (transforming growth factor-β-activated kinase 1), and the adaptor protein TAB1 (TAK-binding protein 1). Inhibition of this late-phase pathway reduced the extent of TNF-α production by mouse macrophages exposed to the TLR4 ligand lipopolysaccharide (LPS) and ameliorated LPS-induced sepsis in mice. Together, these data suggest that TIRAP and IRAK2 are critical for the sustained inflammatory response that is mediated by late-phase signaling by the TLR-4-1BBL complex.