Hepatocyte growth factor (HGF) has been shown to have a unique stimulating property on the endothelium as well as an anti-apoptotic action on the endothelium. Through these mechanisms, HGF has been shown to have an anti-atherogenic action in animal models. In atherosclerotic disorders, the circulating level of HGF has been shown to be increased to compensate for its decline in tissue. However, whether increased circulating HGF has any influence on the development of atherosclerosis has not been elucidated. In the present study, the association between plasma HGF concentration and the risk factor-carotid atherosclerosis relationship was evaluated. Three hundred and seventeen community-dwelling subjects participated in the study. The plasma concentration of HGF was determined by enzyme-linked immunosorbent assay (ELISA). The subjects were divided into two groups according to the plasma level of HGF: a low HGF group (n=199, plasma HGF < 150 pg/ml) and a high HGF group (n=118, plasma HGF > or = 150 pg/ml). Risk factors for atherosclerosis were evaluated in each subject. Carotid ultrasonography was performed to measure carotid arterial intima-media thickness (IMT) and the presence of plaque. The association between carotid IMT and risk factors was then evaluated in the two HGF groups. The regression lines between age and carotid IMT were significantly different between the low HGF and high HGF groups (F[1,313]=5.98, p=0.015). The regression lines between systolic blood pressure and carotid IMT were also significantly different between the two HGF groups (F[1,313]=5.17, p=0.024). A general linear model showed that the interaction between age and plasma level of HGF was significantly associated with carotid IMT, suggesting that the plasma level of HGF modifies the age-related increase in carotid IMT. In addition, clustering of risk factors was evaluated in subjects with carotid atherosclerosis. The number of total risk factors in carotid atherosclerosis subjects with high plasma HGF was significantly greater than that in those with low HGF, even though the two groups had a similar magnitude of carotid atherosclerosis. In conclusion, these findings indicate that risk factor-dependent augmentation of carotid atherosclerosis could be influenced by circulating HGF.