Aim To study the relationship between human cytomegalovirus (HCMV) infection and atherogenesis and the putative mechanism. Methods The HCMV IgG and C-reactive protein (CRP) of subject serum and the existence of HCMV immediate early (IE) gene in the atherosclerotic plaque were detected by enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR). The expression of chemokines in endothelial cells after HCMV infection was also studied. Results The positive ratio of HCMV IgG was significantly higher in atherosclerosis group than that in non-atherosclerosis group (82.2% vs 61.0%, P=0.02); the serum CRP level of atherosclerosis group was significantly higher than that of non-atherosclerosis (5.912±3.795 mg/L vs 2.871±1.761 mg/L, P=0.000); HCMV-specific gene in atherosclerotic plaque was much more frequently detected than that in normal vascular tissue (13/15 vs 2/7, P=0.01). HCMV infection could upregulate the expression of chemokines monocyte chemoattractant protein-1 and fractalkine in endothelial cell ECV-304. Conclusions HCMV infection is involved in the pathogenesis of atherosclerosis, which may be mediated by up-regulated expression of chemokines in ECV-304 after HCMV infection.