Monocyte chemoattractant protein-1 (MCP-1), which mediates the recruitment of monocytes, has been suggested to play a role in atherosclerosis. Because the correlation between circulating MCP-1 and cardiovascular risk has not been thoroughly investigated, we determined the relationship between MCP-1 level and peripheral arterial disease (PAD) or coronary heart disease (CHD). In the Atherosclerosis Risk in Communities (ARIC) study, 209 cases with lower extremity PAD and 412 cases with incident CHD were compared with 733 and 709 subjects without PAD and CHD, respectively. Mean plasma MCP-1 levels were significantly higher in PAD cases (468.7 versus 416.5 pg/mL in non-cases). MCP-1 levels correlated significantly with other inflammatory markers in comparison subjects. Logistic regression analyses showed a significant association of MCP-1 with PAD, independent of traditional CHD risk factors, with an odds ratio of 2.14 (95% CI, 1.28-3.60) for the highest MCP-1 tertile compared with the lowest. Incident CHD risk increased significantly per 1 standard deviation (S.D.) difference in MCP-1 level independent of other cardiovascular risk factors, including inflammatory markers. These data show that MCP-1 is associated with atherosclerotic disease in two vascular beds and suggest that MCP-1 may be a novel target for atherosclerosis therapy.