Inflammasomes are protein complexes promoting caspase activation and processing of IL-1β as well as cell death, in response to infection and cellular stresses. Inflammasomes have been anticipated to contribute to autoimmunity. However, in contrast we find deficiencies in several inflammasome systems in a mouse model of spontaneous autoimmunity. The NZB mouse is genetically susceptible to development of anti-erythrocyte antibodies and is a model of autoimmune haemolytic anemia, and also develop anti-nuclear antibodies typical of lupus. We have shown that NZB macrophages have deficient inflammasome responses to bacterial, viral and fungal infections. AIM2 inflammasome responses are compromised in NZB by high expression of the AIM2 antagonist protein p202. NZB cells had reduced IL-1β output in response to both transfected DNA and mouse cytomegalovirus (MCMV) infection. The inflammasome response to Salmonella infection, largely mediated by NLRC4, was reduced in NZB compared to C57BL/6 cells. Most dramatically, NLRP3 inflammasome function was completely absent in NZB cells. We identified a genetic lesion resulting in NZB being effectively null for nlrp3, with no production of bioactive IL-1β in response to NLRP3 stimuli, including infection with Candida albicans. High inflammasome activity is thus not prerequisite for autoimmunity. We hypothesise that the inflammasome deficiencies in NZB alter the interaction of the host with both microflora and pathogens, promoting prolonged production of cytokines that contribute to development of autoimmunity.