The signaling adapters MyD88 and TRIF are engaged by TLRs and/or receptors of the IL-1 family and are considered important for innate immune responses that combat bacterial infections. Here, the consequences of a combined MyD88 and TRIF deficiency for the innate immune response against severe septic peritonitis was examined. We demonstrate that Myd88(-/-);Trif(Lps2/Lps2) mice had markedly reduced bacterial numbers in the peritoneal cavity and peripheral blood, indicating that bacterial clearance in this model is improved in the absence of MyD88/TRIF signals. Survival of Myd88(-/-); Trif(Lps2/Lps2) mice was improved significantly. The lack of MyD88/TRIF signaling prevented the excessive production of inflammatory cytokines and of IL-10. In contrast, Ifng mRNA was expressed at WT levels, and induction of Ifnb mRNA was reduced only by one-half. Consistent with these findings, numerous IFN-regulated genes, including p47 and p65 GTPases, as well as CXCL10, were expressed in a MyD88/TRIF-independent manner. In support of the in vivo data, Myd88(-/-); Trif(Lps2/Lps2) macrophages stimulated with live intestinal bacteria produced normal amounts of CXCL10. The production of p47 GTPases and CXCL10 in septic peritonitis was found to be dependent on the presence of IFNAR1, but not IFN-γ, indicating a normal induction of the type I IFN response in Myd88(-/-);Trif(Lps2/Lps2) mice, despite attenuated IFN-β production. Together, these results provide evidence that in severe septic peritonitis, the absence of MyD88 and TRIF balances the innate immune response in a favorable manner by attenuating deleterious responses such as excessive cytokine release, while leaving intact protective IFN responses.