Estrogens promote lupus in humans and some mouse models of this disease. Nonetheless, little is known about the role of estrogen receptors in lupus pathogenesis. Here, we report that in females on the lupus-prone (NZB Â NZW)F 1 background, disruption of estrogen receptor-a (ERa or Esr1) attenuated glomerulonephritis and increased survival. ERa deficiency also retarded development of anti-histone/DNA antibodies, suggesting that ERa promotes loss of immunologic tolerance. Furthermore, ERa deficiency in (NZB Â NZW)F 1 females attenuated the subsequent development of anti-double-stranded DNA (dsDNA) IgG antibodies, which are associated with glomerulonephritis in this model. We provide evidence that ERa may promote lupus, at least in part, by inducing interferon-g, an estrogen-regulated cytokine that impacts this disease. ERa deficiency in (NZB Â NZW)F 1 males increased survival and reduced anti-dsDNA antibodies, suggesting that ERa also modulates lupus in males. These studies demonstrate that ERa, rather than ERb, plays a major role in regulating autoimmunity in (NZB Â NZW)F 1 mice. Furthermore, our results suggest for the first time that ERa promotes lupus, at least in part, by impacting the initial loss of tolerance. These data suggest that targeted therapy disrupting ERa, most likely within the immune system, may be effective in the prevention and/or treatment of lupus.