Hyperhomocysteinemia is independently associated with the development of coronary, cerebral and peripheral vascular disease and deep-vein thrombosis in the general population. The evidence that cardiovascular involvement is particularly frequent and advanced in patients affected with several autoimmune diseases (AD), in which hyperhomocysteinemia represent a common finding, led to an intensive investigation on homocysteine (Hcy) as a putative risk factor for the development of cardiovascular disease in such subjects. Indeed, recent data intriguingly expanded the spectrum of the possible pathogenetic implications for hyperhomocysteinemia in the course of AD. In fact, a bi-directional link seems to connect Hcy and the immuno-inflammatory activation characterizing AD, in which immuno-inflammatory activation may contribute to Hcy increase, and Hcy, in its turn, may act as a pro-inflammatory and immuno-stimulating molecule putatively cooperating to the injury of the disease-specific target organs, at least in rheumatoid arthritis and inflammatory bowel disease. Moreover, Hcy may be also a trigger of autoimmune reactions through its capability to bind and structurally modify specific proteins, then resulting in neoantigens formation potentially relevant either in the onset of specific AD and in the progression of the associated cardiovascular damage. More investigation is necessary to fully define the clinical relevance of such phenomena.