AbstractCaspase-1, also known as interleukin-1β (IL-1β)-converting enzyme (ICE), regulates antimicrobial host defense, tissue repair, tumorigenesis, metabolism and membrane biogenesis. On activation within an inflammasome complex, caspase-1 induces pyroptosis and converts pro-IL-1β and pro-IL-18 into their biologically active forms. “ICE−/−” or “Casp1−/−” mice generated using 129 embryonic stem cells carry a 129-associated inactivating passenger mutation on thecaspase-11locus, essentially making them deficient in both caspase-1 and caspase-11. The overlapping and unique functions of caspase-1 and caspase-11 are difficult to unravel without additional genetic tools. Here, we generated caspase-1–deficient mouse (Casp1Null) on the C57BL/6 J background that expressed caspase-11.Casp1Nullcells did not release IL-1β and IL-18 in response to NLRC4 activatorsSalmonellaTyphimurium and flagellin, canonical or non-canonical NLRP3 activators LPS and ATP,Escherichia coli, Citrobacter rodentiumand transfection of LPS, AIM2 activatorsFrancisella novicida, mouse cytomegalovirus and DNA, and the infectious agentsListeria monocytogenesandAspergillus fumigatus. We further demonstrated that caspase-1 and caspase-11 differentially contributed to the host defense againstA. fumigatusinfection and to endotoxemia.