Women have up to a fourfold increase in risk for autoimmune disease compared to men. Many explanations have been proposed, including sex hormones, the X chromosome, microchimerism, environmental factors, and the microbiome. However, the mechanism for this autoimmune sex bias remains obscure. In this manuscript, we evaluate the hypothesis that qualitative or quantitative differences in circulating antibodies may explain, at least in part, the pathogenesis of autoimmune disease and its sex bias—especially when considering an evolutionary perspective. Indeed, women have higher absolute levels of antibodies than men, and (auto)antibodies are also associated with most autoimmune diseases. Several facts suggest differences in antibodies may cause increased prevalence of autoimmune disease in women. First, the association between increased quantities of serum antibodies and increased prevalence of autoimmunity is found not only in women, but also in men with Klinefelter syndrome. Second, both serum antibody levels and autoimmunity spike in the postpartum period. Third, a dose–response effect exists between parity and both serum antibodies and prevalence of autoimmune disease. Fourth, many biologically plausible mechanisms explain the association, such as T cell-dependent activation of B cells and/or VGLL3. The evolutionary underpinning of increased antibodies in women is likely to be protection of offspring from infections. Overall, this evolutionary paradigm can help explain why the phenomenon of autoimmunity occurs preferentially in women and raises the possibility of new treatment options.