Atherosclerosis underlies the development of many cardiovascular diseases that continue to hold a leading place among the causes of death in developed countries. The role of activated immune cells in atherosclerosis progression has been convincingly demonstrated, but the mechanism of their action remains poorly investigated. Since atherosclerosis is associated with chronic inflammatory response, involvement of viral and bacterial infections in atherogenesis has been examined. A special place among the infectious agents is held by human herpesviruses as the most common persistent viruses in human population coupled to chronic inflammation during atherosclerosis. We found that activation of cytomegalovirus (CMV, human herpesvirus 5) infection is associated with the emergence of acute coronary syndrome, which is in a good agreement with the data on productive CMV infection published elsewhere. In this review, we discuss the data obtained by us and other researchers regarding the role of cytomegalovirus infection and related potential mechanisms resulting in the expansion of atherosclerotic plaques during ischemic heart disease and stroke, including virus transfer to immune and endothelial cells via extracellular vesicles. In particular, the data presented in the review demonstrate that virus spreading in the vascular wall triggers immune system activation in atherosclerotic plaques and causes endothelial dysfunction. Moreover, productive CMV infection in patients with acute myocardial infarction correlates with the extent of endothelial dysfunction. The mechanisms described by us and other researchers may explain the role of CMV infection in atherosclerosis and development of ischemic heart disease.