Current knowledge indicates that high plasma levels of fibrinogen, a key protein in the hemostatic system, help predict the major ischemic complications of atherosclerosis, that is, stroke and myocardial infarction. Molecular variations at the fibrinogen genes loci have been shown to regulate fibrinogen concentrations in plasma. However, it is also known that fibrinogen is an acute phase reactant and that its plasma levels are increased by the inflammatory mediator interleukin-6 (IL-6) as a consequence of stimulated gene expression. Certain risk factors for atherosclerosis are known to cause inflammatory and proliferative events within the vessel wall, especially when combined. This raises the question of whether and to what extent high plasma fibrinogen levels in patients with major thrombotic complications of atherosclerosis could be the epiphenomena of as yet poorly elucidated issues in vascular medicine (i.e., severity of vascular damage). Screening of the fibrinogen genes loci in both young patients with established risk factors and in patients evaluated for regression of atherosclerosis who have participated in risk factor reduction programs may provide further insight into the role of genetic factors in the development of atherosclerosis and in the regulation of plasma fibrinogen levels.