Here, we have characterized the first known auto-inflammatory disease caused by interleukin-18 (IL-18). This is due to a point mutation in the gene Wdr1, which is required for disassembly of actin filaments in conjunction with ADF/cofilin family proteins. Mice homozygous for this mutation (Wdr1^rd/rd) develop severe autoinflammation in the ears and tail due to an intracellular build up of polymerized actin. The serum IL-18 level was significantly elevated in Wdr1^rd/rd mice, compared to littermate controls. Processing and secretion of IL-18 and IL-1β is induced by caspase-1 via activation of the inflammasome complex. Importantly, a delayed onset of the disease was seen in Wdr1^rd/rd mice lacking caspase-1, the inflammasome adaptor ASC or IL-18 itself. In contrast, the time of onset and severity of the inflammatory disease was not altered by a deficiency of IL-1R, G-CSF, interferon γ (IFNγ) or tumor necrosis factor α (TNFα), suggesting that the inflammatory disease was driven by an IL-18 specific inflammasome. Furthermore, we are able to show ex vivo and in vivo, that this IL-18 production specifically comes from monocytes, but not mature macrophages. Overall, our data reveal the mechanism and biological basis of a mouse model of spontaneous sterile inflammatory disease driven by IL-18 but not IL-1.