AbstractCryopyrin‐associated periodic syndromes (CAPS) are a spectrum of autoinflammatory disorders caused by gain‐of‐function NLRP3 mutant proteins that form hyperactive inflammasomes leading to overproduction of the pro‐inflammatory cytokines IL‐1β and IL‐18. Expressing the murine gain‐of‐function Nlrp3^A350V mutant selectively in neutrophils recapitulates several autoinflammatory features of human CAPS, but the potential contribution of macrophage inflammasome hyperactivation to CAPS development is poorly defined. Here, we show that expressing Nlrp3^A350V in macrophages is sufficient for driving severe multi‐organ autoinflammation leading to perinatal lethality in mice. In addition, we show that macrophages contribute to autoinflammation also in adult mice, as depleting macrophages in mice ubiquitously expressing Nlrp3^A350V significantly diminishes splenic and hepatic IL‐1β production. Interestingly, inflammation induced by macrophage‐selective Nlrp3^A350V expression does not provoke an influx of mature neutrophils, while neutrophil influx is still occurring in macrophage‐depleted mice with body‐wide Nlrp3^A350V expression. These observations identify macrophages as important cellular drivers of CAPS in mice and support a cooperative cellular model of CAPS development in which macrophages and neutrophils act independently of each other in propagating severe autoinflammation.