MyD88 and MAL are signaling mediators for the Toll-like receptor (TLR) family. MAL acts as a bridging adaptor between TLRs and MyD88, to form ternary complexes through Toll/interleukin-1 receptor (TIR) domain interactions. We found that MAL can either self-assemble or assemble with TLR4 TIR domain into filaments, and that MAL can induce formation of large MyD88 assemblies. A 7 Å resolution cryo-electron microscopy structure of the MAL filament reveals a tube of 12 proto-filaments that consists of two parallel strands of TIR domain subunits in a head-to-tail arrangement. The conserved BB-loop is critical for mediating head-to-tail interactions, and structure-guided mutagenesis, molecular modeling, and mapping of existing signaling mutations confirm that the proto-filament reproduces TIR domain interactions involved in TLR4 signaling. We propose that these interactions, representing TIR:TIR domain association modes in TLR/IL-1R signaling in general, are used to assemble open-ended TLR4:MAL:MyD88 complexes that enable Myddosome formation and IRAK kinase activation.