OBJECTIVE: Recent epidemiologic and animal model data suggest that oxygenated carotenoids are protective against early atherosclerosis. We assessed the association between atherosclerotic progression, measured by carotid intima-media thickness (IMT), and plasma levels of oxygenated and hydrocarbon carotenoids, tocopherols, retinol, and ascorbic acid. METHODS AND RESULTS: Participants were from an occupational cohort of 573 middle-aged women and men who were free of symptomatic cardiovascular disease at baseline. Ultrasound examination of the common carotid arteries, lipid level determination, and risk factor assessment were performed at baseline and 18-month follow-up. Plasma levels of antioxidants were determined at baseline only. Change in IMT was related to baseline plasma antioxidant levels in regression models controlling for co-variates. In models adjusted for age, sex, and smoking status, 18-month change in IMT was significantly inversely related to the 3 measured oxygenated carotenoids (lutein, beta-cryptoxanthin, zeaxanthin; P<0.02 for all) and one hydrocarbon carotenoid, alpha-carotene (P=0.003). After adjusting for additional cardiac risk factors and potential confounders, including high-sensitivity C-reactive protein, these associations remained significant (P<0.05). CONCLUSIONS: These findings suggest that higher levels of plasma oxygenated carotenoids (lutein, zeaxanthin, beta-cryptoxanthin) and alpha-carotene may be protective against early atherosclerosis.