Chronic periodontitis is an inflammatory disease that affects the supporting tissues of the teeth. It is initiated by specific bacteria within the plaque biofilm and progresses due to an abnormal inflammatory-immune response to those bacteria. Periodontitis is the major cause of tooth loss and is also significantly associated with an increased risk of stroke, type-2 diabetes and atheromatous heart disease. Oxidative stress is reported in periodontitis both locally and peripherally (serum), providing potential mechanistic links between periodontitis and systemic inflammatory diseases. It is therefore important to examine serum antioxidant concentrations in periodontal health/disease, both at an individual species and total antioxidant (TAOC) level. To determine whether serum antioxidant concentrations were associated with altered relative risk for periodontitis, we used multiple logistic regression for dual case definitions (both mild and severe disease) of periodontitis in an analysis of 11,480 NHANES III adult participants (>20 y of age). Serum concentrations of vitamin C, bilirubin, and TAOC were inversely associated with periodontitis, the association being stronger in severe disease. Vitamin C and TAOC remained protective in never-smokers. Higher serum antioxidant concentrations were associated with lower odds ratios for severe periodontitis of 0.53 (CI, 0.42,0.68) for vitamin C, 0.65 (0.49,0.93) for bilirubin, and 0.63 (0.47,0.85) for TAOC. In the subpopulation of never-smokers, the protective effect was more pronounced: 0.38 (0.26,0.63, vitamin C) and 0.55 (0.33,0.93, TAOC). Increased serum antioxidant concentrations are associated with a reduced relative risk of periodontitis even in never-smokers.