IRAK1 is a key regulatory protein in TLR/IL1R-mediated cell activation during the inflammatory response. Studies indicated that pending on the nature of the used inflammatory model, down-regulation of IRAK1 may be beneficial or detrimental. However the role of IRAK1 in affecting outcome in polymicrobial sepsis is unknown. We tested this question using an IRAK1 deficient mouse strain and the cecal ligation and puncture (CLP) procedure, which is a clinically relevant rodent septic model. Sepsis-induced mortality was markedly lower in IRAK1-deficient mice (35%) compared to WT (85%). Sepsis-induced increases in blood IL-6 and IL-10 levels were blunted at 6h post-CLP in IRAK1 deficiency compared to WT but cytokine levels were similar at 20h post-CLP. Sepsis induced blood granulocytosis and depletion of splenic B cells were also blunted in IRAK1 deficient mice as compared to WT. Analysis of TLR-mediated cytokine responses by IRAK1 deficient and WT macrophages ex vivo indicated a TLR4-dependent down-regulation of IL-6 and IL1β in IRAK1 deficiency, whereas TLR2 dependent responses were unaffected. TLR7/8-mediated IL-6, IL1β and IL-10 production was also blunted in IRAK1 macrophages as compared to WT. The study shows that IRAK1 deficiency impacts multiple TLR-dependent pathways and decreases early cytokine responses following polymicrobial sepsis. The delayed inflammatory response caused by the lack of IRAK1 expression is beneficial, as it manifests a markedly increased chance of survival after polymicrobial sepsis.