Spleen tyrosine kinase (Syk) is a non-receptor protein tyrosine kinase, which is known to be involved in adaptive and innate immune signalling. A prototypical Syk recruitment mechanism to cell surface has been well characterised in ITAM-based immunoreceptor signalling pathways, which includes the T cell receptors, B cell receptor and Fc receptors. In these cases, Syk is activated by binding of its two SH2 domains to appropriately spaced phosphorylated tyrosine motifs. However, TLR4 has no conserved ITAM motif, therefore the underlying mechanism for Syk activation and recruitment to TLR4 is not known. One possibility is that the Syk-TLR association is indirect, relying on a scaffolding protein. In our study, we identified the transmembrane adaptor SCIMP, a member of the pTRAP family, plays such a role in bridging Syk to TLR4 for regulating TLR4 phosphorylation and generating pro-inflammatory responses. Mechanistically, we showed that two phosphorylated tyrosines (Y96 and Y120) of SCIMP serve as binding sites for N-SH2 and C-SH2 domains of Syk, thus tethers to Syk. Activated Syk subsequently functions to phosphorylate both TLR4 and SCIMP. In addition, phosphorylation of each signalling molecule by Syk also stabilised the association of the TLR4-SCIMP-Syk ternary complex. These results provide evidence that Syk activity and scaffolding role of SCIMP are both indispensable for TLR signal transduction. Therefore, we identified SCIMP as a novel Syk scaffold, which helps to propagate TLR4 signal transduction and inflammation.