Danger signals activate Toll-like receptors (TLRs)， thereby initiating inflammatory responses. Canonical TLR signalling， via Toll/Interleukin-1 receptor domain (TIR)-containing adaptors and proinflammatory transcription factors such as NF-κB， occurs in many cell types; however， additional mechanisms are required for specificity of inflammatory responses in innate immune cells. Here we show that SCIMP， an immune-restricted， transmembrane adaptor protein (TRAP)， promotes selective proinflammatory cytokine responses by direct modulation of TLR4. SCIMP is a non-TIR-containing adaptor， binding directly to the TLR4-TIR domain in response to lipopolysaccharide. In macrophages， SCIMP is constitutively associated with the Lyn tyrosine kinase， is required for tyrosine phosphorylation of TLR4， and facilitates TLR-inducible production of the proinflammatory cytokines IL-6 and IL-12p40. Point mutations in SCIMP abrogating TLR4 binding also prevent SCIMP-mediated cytokine production. SCIMP is， therefore， an immune-specific TLR adaptor that shapes host defence and inflammation.