AbstractSystemic lupus erythematosis is an autoimmune disease of unknown etiology. Lupus pathology is thought to reflect autoantibody‐mediated damage due to a failure of B lymphocyte tolerance. Since excessive B cell‐activating factor belonging to the TNF family (BAFF) expression correlates with human and murine lupus, and BAFF signals B cell survival through BAFF‐R, it is believed that excessive BAFF‐R signaling can subvert B cell tolerance and facilitate lupus development. Here we report the unexpected finding that BAFF‐R‐mutant A/WySnJ mice develop a lupus‐like syndrome. These mice carry the B cell maturation defect‐1 (Bcmd‐1) mutant allele of the Baffr gene. Bcmd‐1 causes premature B cell death and profound B cell deficiency. Despite having 90% fewer splenic B cells than normal mice, A/WySnJ mice had an 18‐fold increased frequency of splenocytes secreting IgM antibodies to dsDNA, and increased amounts of circulating IgM and IgG to dsDNA by 9 months of age. By age 11 months, most A/WySnJ mice displayed renal pathology characteristic of lupus, including proteinuria as well as periodic acid‐Schiff‐positive deposits and glomerular capillary bed destruction. Importantly, we genetically linked this autoimmunity to Bcmd‐1, since congenic AW.Baffr+/+ mice carrying a wild‐type allele developed none of these phenotypes. Our data provide the first evidence linking altered BAFF‐R signaling to the development of B cell‐mediated autoimmunity.