Atherosclerosis is a chronic inflammatory disease of arteries, associated with multiple genetic and environmental factors, including hypertension, diabetes mellitus, cigarette smoking, modified and elevated LDL cholesterol, elevated plasma homocysteine, and infectious microorganisms such as Chlamydia pneumoniae and cytomegalovirus (CMV). CMV has been implicated in atherogenesis by epidemiological studies, animal research, and molecular analyses that have demonstrated CMV nucleic acids within human atherosclerotic lesions. Studies have suggested that CMV infection may alter lipid metabolism and lead to accumulation of cholesterol within atheromatous plaques. Few studies have examined the relationship between CMV infection and serum cholesterol levels in younger individuals when much of atherogenesis occurs. To test if CMV-seropositivity is associated with high levels of serum total cholesterol in relatively young patients, CMV IgG levels and total cholesterol concentrations were analyzed in serums from 172 patients, age <50 yr. Based on univariate analysis of variance, serum total cholesterol was significantly correlated to age and to CMV-seropositivity when gender was a cofactor, but not to gender or CMV-seropositivity alone. In 39 CMV-seropositive women, serum total cholesterol concentration averaged 218 <plus/minus> 50 mg/dL (mean +/- SD), which was significantly higher than in 53 CMV-seronegative women (194 +/- 39 mg/dL, p <0.02). No significant difference was observed between the serum total cholesterol concentrations in 26 CMV-seropositive men and 51CMV-seronegative men (198 <plus/minus> 42 mg/dL versus 212 +/- 48 mg/dl, respectively). Thus, this study provides evidence that CMV-seropositivity is associated with higher serum total cholesterol levels in female patients under 50 yr of age, but not in male patients of comparable age. (received 22 December 2000; accepted 15 February 2001).