Salmonella typhimurium invades host macrophages and induces apoptosis and the release of mature proinflammatory cytokines. SipB, a protein translocated by Salmonella into the cytoplasm of macrophages, is required for activation of Caspase-1 (Casp-1, an interleukin [IL]-1β–converting enzyme), which is a member of a family of cysteine proteases that induce apoptosis in mammalian cells. Casp-1 is unique among caspases because it also directly cleaves the proinflammatory cytokines IL-1β and IL-18 to produce bioactive cytokines. We show here that mice lacking Casp-1 ( casp-1 −/ − mice) had an oral S . typhimurium 50% lethal dose (LD 50 ) that was 1,000-fold higher than that of wild-type mice. Salmonella breached the M cell barrier of casp-1 −/ − mice efficiently; however, there was a decrease in the number of apoptotic cells, intracellular bacteria, and the recruitment of polymorphonuclear lymphocytes in the Peyer's patches (PP) as compared with wild-type mice. Furthermore, Salmonella did not disseminate systemically in the majority of casp-1 −/ − mice, as demonstrated by significantly less colonization in the PP, mesenteric lymph nodes, and spleens of casp-1 −/ − mice after an oral dose of S . typhimurium that was 100-fold higher than the LD 50 . The increased resistance in casp-1 −/ − animals appears specific for Salmonella infection since these mice were susceptible to colonization by another enteric pathogen, Yersinia pseudotuberculosis , which normally invades the PP. These results show that Casp-1, which is both proapoptotic and proinflammatory, is essential for S . typhimurium to efficiently colonize the cecum and PP and subsequently cause systemic typhoid-like disease in mice.