Innate immune and inflammatory responses are triggered by pathogen or damage activation of Toll-like (TLR) receptors. We have previously shown that the immune-specific transmembrane adaptor SCIMP is a regulator of TLR signalling and pro-inflammatory responses in macrophages1,2. SCIMP directly binds TLRs through a non-canonical, TIR-non-TIR interaction, scaffolding the Src family kinase, Lyn, for TLR activation and driving the selective production of IL-6 and IL-12p40, but the mechanism for the selectivity of these cytokine outputs was not known. Using mass spectrometry, affinity pull downs and co-immunoprecipitation in macrophage lysates we identify Erk1/2 as a novel binding partner of SCIMP. BMMs from SCIMP KO mice show the requirement for SCIMP in Erk-mediated production of pro-inflammatory IL-1b, IL-2 and TNF but not for anti-inflammatory cytokines or chemokines. High-resolution live imaging shows that SCIMP recruits Erk to signalling domains on cell surface ruffles in an LPS-inducible manner. SCIMP-scaffolded Erk1/2 enhances nuclear translocation of c-Fos for transcriptional activation. Thus, we identify a mechanism by which SCIMP recruits Erk1/2 for c-Fos activation in pro-inflammatory TLR signalling in macrophages. From this, SCIMP emerges as a novel, immune specific scaffold for Erk1/2 kinase with important roles in inflammation and infection. SCIMP is genetically associated with human autoimmune and chronic inflammatory diseases including SLE and Alzheimer’s disease, highlighting the SCIMP/Erk/c-Fos axis as a possible therapeutic target.