90% of patients with the autoimmune disease systemic lupus erythematosus (SLE) are female, but mechanisms that underly this sex bias are not understood. Klinefelter’s males (XXY) and polysomy X females (XXX) are overrepresented in cohorts of patients with SLE, suggesting that increasing X chromosomal dosage heightens the risk of developing SLE. The X chromosome encodes numerous immune regulatory genes, but X-linked gene expression is balanced between female and male mammals via X Chromosome Inactivation (XCI). XCI is regulated by association of the long non-coding RNA XIST/Xist and other repressive epigenetic modifications with one inactive X chromosome (Xi) in every female cell. The Xi is mostly transcriptionally silent, although some genes can “escape” silencing and are biallelically expressed from both X chromosomes. In B cells from female patients and mice with SLE, XIST/Xist RNA localization on the Xi is disrupted and some X-linked genes are aberrantly expressed, suggesting that XCI is perturbed, which may contribute to the female sex bias in SLE. Here, I experimentally disrupt XCI by deleting Xist in the B cell compartment of female mice (“Xist cKO”). I find that some Xist cKO mice spontaneously develop SLE-like disease, and Xist cKO mice develop more severe features of induced SLE. B cells from Xist cKO mice with SLE phenotypes have increased expression of X-linked genes, including an immune regulatory gene with defined roles in human and mouse SLE. Finally, I quantify escape from the Xi in B cells from mice with induced SLE-like disease. This body of work defines epigenetic and transcriptional mechanisms at play on the X chromosome in autoimmunity and demonstrates that disrupted XCI causes SLE-like disease, highlighting a likely mechanism contributing to the female sex bias in patients with SLE.