Systemic lupus erythematosus (SLE) occurs nine times more often in females than males. The purpose of this study was to determine the impact of estrogen receptor (ER) null genotypes on disease in lupus prone NZM2410 (NZM) and MRL/lpr mice, as a method to define the role of estrogen receptor signaling in lupus. ER alpha deficient NZM females, but not males, had significantly prolonged survival, reduced proteinuria, renal pathology scores and serum urea nitrogen levels compared to wildtype mice, despite higher serum anti-dsDNA levels. ER alpha deficient MRL/lpr female, but not male, mice also had significantly less proteinuria and renal pathology scores with no effect on autoantibody levels. Deficiency of ER beta had no effect on disease in either strain or sex. Taken together, these data demonstrate a key role for ER alpha, but not ER beta, in the development of lupus like disease, but not autoimmunity, in female NZM and MRL/lpr mice.