Infection has long been implicated as a trigger for autoimmune disease. Other antigenic challenges include receipt of allogeneic tissue or blood resulting in immunomodulation. We investigated antigenic challenges as possible risk factors for autoimmune disease in women using the Health and Retirement Study, a nationally representative longitudinal study, linked to Medicare files, years 1991–2007. The prevalence of autoimmune disease (rheumatoid arthritis, Hashimoto’s disease, Graves’ disease, systemic lupus erythematosus, celiac disease, systemic sclerosis, Sjögren syndrome and multiple sclerosis) was 1.4% in older women (95% CI: 1.3%, 1.5%) with significant variation across regions of the United States. The risk of autoimmune disease increased by 41% (95% CI of incidence rate ratio (IRR): 1.10, 1.81) with a prior infection-related medical visit. The risk of autoimmune disease increased by 90% (95% CI of IRR: 1.36, 2.66) with a prior transfusion without infection. Parity was not associated with autoimmune disease. Women less than 65 years of age and Jewish women had significantly elevated risk of developing autoimmune disease, as did individuals with a history of heart disease or end-stage renal disease. Antigenic challenges, such as infection and allogeneic blood transfusion, are significant risk factors for the development of autoimmune disease in older women.