Background: Serum carotenoid concentrations relate inversely to cardiovascular disease incidence. To clarify the effect of carotenoids on atherosclerotic risk factors, we examined the association of circulating carotenoids with inflammation, oxidative stress, endothelial dysfunction, and smoking. Methods: Black and white men and women in the Coronary Artery Risk Development in Young Adults study, ages 18 to 30 years at recruitment (1985-1986) from 4 US cities, were investigated over 15 years. We included 2048 to 4580 participants in analyses of the sum of serum α-carotene, β-carotene, zeaxanthin/lutein, and β-cryptoxanthin concentrations and of lycopene at year 0 and at year 7. Results: The year 0 sum of 4 carotenoids was inversely associated (all P <0.05) with year 0 leukocyte count (slope per sum carotenoid SD, -0.17); year 7 fibrinogen (slope, -0.10); year 7 and year 15 C-reactive protein (slope, -0.12 and -0.09); and year 15 F2- isoprostanes (slope, -13.0), soluble P-selectin (slope, -0.48), and soluble intercellular adhesion molecule-1 (sICAM1; slope, -5.1). Leukocyte counts and sICAM1 and F2-isoprostane concentrations had stronger associations in smokers than in nonsmokers, and sICAM1 concentrations were higher in the highest carotenoid quartile in smokers than in the lowest carotenoid quartile in nonsmokers. Superoxide dismutase was positively associated with the sum of 4 carotenoids (slope, 0.12; P <0.01). Lycopene was inversely associated only with sICAM1. The year 7 carotenoid associations with these markers were mostly similar to those at year 0. Conclusions: Circulating serum carotenoids were associated, some interactively with smoking, in apparently beneficial directions with markers of inflammation, oxidative stress, and endothelial dysfunction.