Over the last couple of decades, the paradigm of premature immunosenescence in systemic autoimmune diseases such as rheumatoid arthritis (RA) has emerged1, 2. The theory of immunosenescence suggests that immune dysfunction with aging is associated with increased autoantibody production. However, it is not entirely clear whether autoantibodies are innocent bystanders of the aging process or whether they play an important role in chronic diseases of aging such as atherosclerosis. There is evidence that certain autoantibodies may act directly in the pathogenesis of atherosclerosis. The role of autoantibodies in atherosclerosis and aging is particularly intriguing because there is an increased risk of cardiovascular (CV) disease and mortality in systemic autoimmune diseases, frequently associated with autoantibody production, that is not explained by traditional risk factors for atherosclerosis alone3-10. Further, recent evidence suggests that systemic autoimmune diseases may be associated with premature immunosenescence1, 2, 11. Could the autoantibodies produced through premature immunosenescence in systemic autoimmune diseases explain the increased atherosclerosis and CV mortality in these diseases? To examine this question, we review the current literature in the following areas:(1) the theory of immunosenescence and the role of autoantibodies in this process;(2) the role of autoantibodies in atherosclerosis and CV disease;(3) premature immunosenescence in systemic autoimmune diseases; and (4) prevalence studies of autoantibodies in the healthy elderly, which seem to support an “innocent bystander” effect of autoantibodies in select individuals.