Atherosclerosis is a chronic inflammatory disease of the arterial wall that is influenced by several risk factors, including hyperlipidemia and hypertension. Autoimmune diseases substantially increase the risk for cardiovascular disease (CVD). Although atherosclerotic CVD, such as myocardial and stroke, is much more prevalent than classical autoimmune conditions such as rheumatoid arthritis, psoriasis, and systemic lupus erythematosus, these types of pathology have many similarities, raising the possibility that therapies against autoimmune disease can have beneficial effects on CVD. Substantial clinical and experimental data support the potential for immunomodulatory approaches to combating both autoimmune and cardiovascular diseases, including classical immunosuppressants, anticytokine therapy, the targeting of T and B cells and their responses, and vaccination. In this review, we discuss experimental and clinical studies that have used immunomodulatory approaches to mitigate autoimmune reactions and examine their potential to prevent and treat atherosclerotic CVD.