Caspase‐1 [IL‐1β‐converting enzyme (ICE)] processes substrate precursor molecules to yield the biologically active form of IL‐1β and IL‐18, both of which are considered to play important roles in the host defense by activation of both innate and adaptive immunity. We evaluated the immune response of caspase‐1–/– mice to Listeria monocytogenes (LM) infection. LM eradication in the early phase of infection was impaired in the mutant mice with a prominent decrease in IL‐18 and IFN‐γ production, but not in IL‐12. Caspase‐1–/– spleen cells including dendritic cells and NK cells produced less IFN‐γ in response to heat‐killed LM than wild‐type cells in vitro. IFN‐γ production and bactericidal activity in LM‐infected caspase‐1–/– mice was reconstituted to normal levels by adding back IL‐18 at the initial phase of infection, suggesting that the lack of this cytokine is primarily responsible for the susceptibility of caspase‐1–/– mice against LM infection. Moreover, IFN‐γ injection of caspase‐1–/– mice corrected the deficiency in pathogen clearance. In contrast, LM‐specific acquired immunity in caspase‐1–/– mice was normal and they successfully cleared the pathogen following secondary infection, in spite of a moderate skewing of cytokine profile to Th2 when compared to wild‐type mice. These data shed light on the importance of caspase‐1‐mediated IL‐18 processing in innate immunity against facultative intracellular pathogens.