Significance IFN regulatory factor 3 (IRF3) is one of the most well-characterized transcription factors involved in the regulation of innate immune responses. Many studies have used conventional Irf3 -deficient mice to analyze the functions of IRF3 in immunity and other biological systems; however, these mice were found to carry another null mutation in the Bcl2l12 gene, which has confounded the analyses of these mice. For this study, we generated conditional Irf3 -deficient mice while leaving the Bcl2l12 gene intact. Conditional ablation of IRF3 in myeloid cells showed increased survival when challenged with endotoxin-induced shock, indicating a myeloid cell-specific role of IRF3. The IRF3 conditional knockout mouse may be a useful tool to identify cell type-specific functions of this transcription factor.