The adaptor Mal is crucially involved in TLR4 and TLR2 signal transduction via the recruitment of MyD88 to the plasma membrane.  Mal is known to have eight non-synonymous single nucleotide polymorphisms (SNPs) in its coding region. Previous studies using overexpression systems suggest the Mal D96N SNP is associated with reduced NF-κB activation and cytokine production via the inability of Mal to recruit MyD88. Here with the use of the recently generated D96N mouse we aim to characterise the effect of Mal D96N on TLR signalling and the biological outcomes of this during bacterial and viral infection. Bone marrow derived macrophages (BMDMs) from D96N mice display reduced inflammatory responses to the TLR4 ligand lipopolysaccharide (LPS). Macrophages from Mal D96N mice produced significantly less IL-6 and TNFα with no effect on LPS-induced IFNβ. Delayed MAP kinase activation and phosphorylation of NF-κB subunit p65 was also observed in D96N macrophages in response to both LPS and the TLR2 ligand Pam₃Cys. Furthermore, Mal D96N mice are protected from LPS-induced lethality. Data suggests reduced levels of IL-6 in the serum of D96N mice at early time points following administration of LPS (i.p). Future work will focus on examining the interaction of Mal D96N with MyD88 and its recruitment to the membrane following TLR4 and TLR2 activation. While Mal knock-out mice display ablated inflammation, studies with the D96N mouse will provide insight as to the non-bridging effects of Mal in TLR signalling during inflammation.