Potential antiinflammatory and antioxidant effects were recently ascribed to naturally occurring micronutrients. The extent and magnitudes of their differential effects on the metabolic syndrome (MetS) are still unknown. We examined the association between serum antioxidant status and MetS. NHANES 2001-2006 cross-sectional data among adults aged 20-85 y were analyzed (n = 3008-9099). MetS was defined with the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) and also by elevated homeostatic model assessment insulin resistance (HOMA-IR), C-reactive protein (CRP) and hyperuricemia. Serum antioxidants included retinol, retinyl esters, carotenoids [α-carotene, β-carotene (cis+trans), β-cryptoxanthin, lutein+zeaxanthin, total lycopene], vitamin E, and vitamin C. MetS (NCEP ATP III) prevalence in U.S. adults was 32.0% among men and 29.5% among women. Adults with MetS had consistently lower serum carotenoid concentrations compared with those without MetS, even after controlling for total cholesterol and TG among other potential confounders. Vitamin E had no significant relationship with MetS in the full multiple logistic regression model, whereas retinol+retinyl esters were inversely related to MetS among men only. The latter were also inversely related to elevated CRP and positively associated with hyperuricemia. Vitamin C exhibited a similar pattern to serum carotenoids with an inverse linear association with MetS (binary), HOMA-IR, and hyperuricemia. Future intervention studies of dietary and lifestyle change must be conducted to assess the utility of modifying serum antioxidant concentrations, especially carotenoids, given their suboptimal levels among U.S. adults with MetS, for the prevention of type 2 diabetes and various cardiovascular endpoints.