Mutations in the gene encoding pyrin are associated with autoinflammatory disorder Familial Mediterranean Fever (FMF). A FMF-knock-in mouse strain that expresses chimeric pyrin protein with a V726A mutation (Mefv^V726A/V726A) was generated to model human FMF. This mouse strain shows an autoinflammatory disorder that is prevented by genetic deletion of IL-1 (IL-1) receptor or apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC). ASC-mediated cell death leads to the release of IL-1α and IL-1β, both of which signal through IL-1 receptor. Furthermore, caspase-1 and caspase-8 can interact with ASC to mediate secretion of IL-1 cytokines. The specific IL-1 cytokine instigating development of FMF and the enzymatic caspase involved in its secretion currently are unknown. In this study, we show that the autoinflammation observed in Mefv^V726A/V726A mice is mediated specifically by IL-1β and not IL-1α. Furthermore, the disorder is dependent on the caspase-1–ASC axis, whereas caspase-8 is dispensable. Concurrently, aberrant IL-1β release by Mefv^V726A/V726A monocytes in response to stimulation with lipopolysaccharide also is dependent on the caspase-1–ASC axis. In conclusion, our studies have uncovered a specific role for caspase-1–mediated IL-1β release in the manifestation of FMF.