Background—Recent findings suggest a causative role of infections in the pathogenesis of atherosclerosis. In hypothesizing an association between infectious agents and the development of atherosclerosis, we would expect a correlation to the extent of atherosclerosis. Moreover, this effect could be multiplied by the number of pathogens to which an individual had been exposed.Methods and Results—In 572 patients, IgG or IgA antibodies to herpes simplex virus 1 and 2, cytomegalovirus, Epstein-Barr virus,Hemophilus influenzae,Chlamydia pneumoniae,Mycoplasma pneumoniae, andHelicobacter pyloriwere measured. The extent of atherosclerosis was determined by coronary angiography, carotid duplex sonography, and evaluation of the ankle-arm index. Elevated IgA antibodies againstC pneumoniae(P<0.04) and IgG antibodies againstH pylori(P<0.02), cytomegalovirus (P<0.05), and herpes simplex virus 2 (P<0.01) were associated with advanced atherosclerosis (≥2 vascular regions), adjusted for age, sex, cardiovascular risk factors, and highly sensitive C-reactive protein. Infectious burden divided into 0 to 3, 4 to 5, and 6 to 8 seropositivities was significantly associated with advanced atherosclerosis, with an odds ratio (95% CI) of 1.8 (1.2 to 2.6) for 4 to 5 (P<0.01) and 2.5 (1.2 to 5.1) for 6 to 8 seropositivities (P<0.02) (adjusted). After a mean follow-up of 3.2 years, cardiovascular mortality rate was 7.0% in patients with advanced atherosclerosis and seropositive for 0 to 3 pathogens compared with 20.0% in those seropositive for 6 to 8 pathogens.Conclusions—Our results support the hypothesis that infectious agents are involved in the development of atherosclerosis. We showed a significant association between infectious burden and the extent of atherosclerosis. Moreover, the risk for future death was increased by the number of infectious pathogens, especially in patients with advanced atherosclerosis.