Studies of interleukin-6 (IL-6) and C-reactive protein (CRP) as predictors of atherosclerosis have had mixed results. The purpose of this study was to assess the associations of IL-6 and CRP with the severity of subclinical carotid atherosclerosis measured 12 years later. Participants were 392 adults (56.9% women, mean age 63.2 years) from the Rancho Bernardo Study who had biomarkers measured from 1984 to 1987 and carotid intima-media thickness (IMT) measured from 1996 to 1998. Age-adjusted mean carotid IMT was significantly greater in men than women. After adjusting for traditional cardiovascular risk factors, carotid IMT increased significantly with increasing IL-6 quartiles (p <0.001). In similar analyses, the association between CRP quartiles and carotid IMT was weaker but remained statistically significant (p <0.05). In multiple regression analysis, IL-6 was significantly associated with carotid IMT regardless of CRP. Conversely, CRP was significantly associated with carotid IMT when IL-6 was not included in the model, but this association became nonsignificant when IL-6 was included. In conclusion, baseline IL-6 and CRP were significantly associated with carotid atherosclerosis independent of traditional cardiovascular disease risk factors. The association of IL-6 was independent of CRP, but not vice versa, suggesting an effect of IL-6 on an earlier state of atherosclerosis.