The recognition of microbial pathogens by the innate immune system involves Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns1-9. Different TLRs recognize different pathogen-associated molecular patterns, with TLR-4 mediating the response to lipopolysaccharide from Gram-negative bacteria5-7. All TLRs have a Toll/IL-1 receptor (TLR) domain, which is responsible for signal transduction1,2. MyD88 is one such protein that contains a TlR domain10,11. It acts as an adapter, being involved in TLR-2, TLR-4 and TLR-9 signalling12-15; however, our understanding of how TLR-4 signals is incomplete15,16. Here we describe a protein, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TlR-domain-containing protein in the human genome. Mal activates NF-κB, Jun amino-terminal kinase and extracellular signal-regulated kinase-1 and -2. Mal can form homodimers and can also form heterodimers with MyD88. Activation of NF-κB by Mai requires IRAK-2, but not IRAK, whereas MyD88 requires both IRAKs. Mal associates with IRAK-2 by means of its TlR domain. A dominant negative form of Mal inhibits NF-κB, which is activated by TLR-4 or lipopolysaccharide, but it does not inhibit NF-κB activation by IL-1RI or IL-18R. Mal associates with TLR-4. Mal is therefore an adapter in TLR-4 signal transduction.