Somatically mutated high-affinity autoantibodies are a hallmark of some autoimmune diseases, including systemic lupus erythematosus. It has long been presumed that germinal centers (GCs) are critical in autoantibody production, because they are the only sites currently believed to sustain a high rate of somatic hypermutation. Contrary to this idea, we found that splenic autoreactive B cells in autoimmune MRL.Fas^lpr mice proliferated and underwent active somatic hypermutation at the T zone–red pulp border rather than in GCs. Our results implicate this region as an important site for hypermutation and the loss of B cell self-tolerance.