Autoimmunity is largely prevented by medullary thymic epithelial cells (TECs) through their expression and presentation of tissue-specific Ags to developing thymocytes, resulting in deletion of self-reactive T cells and supporting regulatory T cell development. The transcription factor has been implicated in autoimmune diseases in humans through genome-wide association studies and in mice using cell type-specific deletion of in T and dendritic cells. In this article, we demonstrate that Prdm1 functions in TECs to prevent autoimmunity in mice. Prdm1 is expressed by a subset of mouse TECs, and conditional deletion of in either or expressing cells in mice resulted in multisymptom autoimmune pathology. Notably, the development of Foxp3 regulatory T cells occurs normally in the absence of Blimp1. Importantly, nude mice developed anti-nuclear Abs when transplanted with null TECs, but not wild-type TECs, indicating that functions in TECs to regulate autoantibody production. We show that acts independently of Aire, a crucial transcription factor implicated in medullary TEC function. Collectively, our data highlight a previously unrecognized role for Prdm1 in regulating thymic epithelial function.