RA is characterized by a systemic inflammatory state, in which immune cells and soluble mediators play a crucial role. These inflammatory processes resemble those in other chronic inflammatory diseases, such as atherosclerosis. The chronic systemic inflammation in RA can be considered as an independent risk factor for the development of atherosclerosis, and represents an important field to investigate the reasons of the increase of acute cardiovascular events in RA. In the present review, we focused on several mediators of autoimmunity, inflammation and endothelial dysfunction, which can be considered the most promising targets to prevent atherogenesis in RA. Among several mediators, the pro-inflammatory cytokine TNF-alpha has been shown as a crucial factor to induce atherosclerosis in RA patients.