Vascular injury is an initiating event in the development of atherosclerosis and herpesviruses have been proposed as potential mediators of vascular injury. The demonstration that an avian herpesvirus could induce atherosclerosis in chickens [Fabricant CG, Fabricant J, Litrenta MM, Minick CR. Virus induced atherosclerosis. J Exp Med 1978;148:335-340; Fabricant CG, Fabricant J, Minick CR, Litrenta MM. Herpes virus induced atherosclerosis in chickens. Fed Proc 1983;42:2476-2479; Minick CR, Fabricant CG, Fabricant J, Litrenta MM. Atheroarteriosclerosis induced by infection by herpesvirus. Am J Pathol 1978;96:673-706] suggested the potential of these viral agents to cause similar lesions in humans. In addition, epidemiological evidence linking herpesvirus infection and atherosclerosis [Cunningham MJ, Pasternak RC. The potential role of viruses in the pathogenesis of atherosclerosis. Circulation 1988;77:964-996; Melnick JL, Adam E, DeBakey ME. Cytomegalovirus and atherosclerosis. BioEssays 1995;17:899-903; Adam E, Melnick JL, Probesfield JL et al. High levels of cytomegalovirus antibody in patients requiring vascular surgery for atherosclerosis. Lancet 1987;2:291-293] adds further credence to their role as possible etiologic agents. However, the link between herpesviruses and vascular thrombosis is more tenuous. In this review, we highlight some recent advances in this field, from our laboratory and others, to support the hypothesis that herpesviruses act as prothrombotic agents by activating the coagulation cascade.