Atherosclerosis is initially a chronic inflammatory disease as it involves inflammatory cells such as macrophages, T-lymphocytes and mast cells. At later stages, when plaques manifest clinically, thrombosis, coagulation and fibrinolysis contribute to the escalation of the disease, which culminates in acute cardiovascular syndromes. Serine proteases are instrumental in all of these processes, rendering their inhibition of clinical interest for the prevention of atherosclerotic plaque progression. Viral serine protease inhibitors, specifically engineered by pathogens to evade the host's defense system, not only display profound anti-inflammatory activity but also inhibit a range of serine proteases implicated in cardiovascular disease. In this review, the potential of viral serine protease inhibitors in anti-atherosclerotic therapy is discussed.