MAL and MyD88 are signaling mediators for Toll-like receptors (TLRs) and form ternary complexes through TIR (Toll/interleukin-1 receptor [IL-1R]) domain interactions. We demonstrate that MAL can self-assemble or assemble with TLR4 into filaments, and that MAL induces formation of 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 BB loop-mediated head-to-tail arrangement. Structure-guided mutagenesis, combined with cellular clustering assays, confirms that the proto-filament reproduces TIR:TIR interactions in TLR4 signaling. Our data suggest a signaling model that involves open-ended TLR4:MAL:MyD88 complexes, and explains the all-or-none TLR signaling responses. The conservation of residues involved in TIR:TIR interactions suggests analogous association modes in TLR/IL-1R signaling in general.