Abstract Lupus is a disease that disproportionately affects females. We previously showed that a functional knockout of estrogen receptor alpha (ERαKO) resulted in significantly reduced renal disease and increased survival in murine lupus. Dendritic cell development, which requires both estrogen and ERα is impacted, as is activation status and cytokine production. Due to altered hormonal feedback loops, ERαKO mice have hypergonadism and partial endocrine sex reversal. Elevated estrogen (E2) and testosterone levels may have immunomodulating effects. Thus, we studied the phenotype of the lupus-prone ERαKO mouse following ovariectomy (OVX) +/- E2 replacement to preserve a physiologic hormonal state. We found that NZM2410 ERαKO mice were protected from lupus disease expression (no early deaths; no proteinuria at 32 weeks) if they were either unmanipulated or if they were both ovariectomized and E2-repleted. These mice also had fewer inflammatory and activated cDCs (CD11c+/CD11b+/MHCII+ cells from Flt3L-cultured bone marrow, or ex vivo spleen or kidney cells), which correlated with increased survival. Interestingly, protection was lost after ovariectomy if no E2 pellet was administered, suggesting that the protective effect requires E2 in the system (despite the lack of a functional ERα). A protective effect was not observed in lupus-prone Ex3a mice (ERα−/−) suggesting that the functional mutant in ERαKO mice, in the presence of estrogen, potentially modulates disease.