Current evidence indicates that plasma fibrinogen is synthesized by the liver; that genetic and environmental factors regulate plasma fibrinogen levels; that interleukin-6 (IL-6) affects the synthesis of plasma fibrinogen by mechanisms involving protein kinase C, and that during the acute-phase response, monocytes generate a variety of monokines including IL-6. Certain drugs and nutrients have been reported to lower plasma fibrinogen levels. The mechanism(s) involved in this effect is poorly understood. However, since most of these substances quantitatively and/or qualitatively affect monocytes, the possibility that these drugs affect plasma fibrinogen levels via these cells should be considered. In addition to fibrinogen, IL-6 also regulates the synthesis of other acute-phase proteins. Especially when combined, major risk factors for atherosclerosis cause vascular injury that triggers inflammatory events. This raises the issue of whether high plasma fibrinogen levels are just the epiphenomenon of as yet unknown events in thrombosis and atherosclerosis. Thus, the issue to be addressed is whether high plasma fibrinogen concentrations should be lowered or should they serve to suggest strong interventions on established risk factors. As for other risk factors, fibrinogen measurements in population-based studies, in parallel with measurements of established risk factors will help define appropriate directions to be followed to gain insight into the issue and define new antithrombotic strategies.