Tocopherols are lipid-soluble antioxidants that may protect against some conditions of aging. The authors examined associations between radiographic knee osteoarthritis and serum levels of alpha-, delta-, and gamma-tocopherol and the alpha:gamma-tocopherol ratio in African-American and White adults from the Johnston County Osteoarthritis Project (North Carolina, 1991-1997). Two hundred cases with radiographic knee osteoarthritis (Kellgren-Lawrence grades > or = 2) and 200 controls (Kellgren-Lawrence grade 0) were randomly selected and matched by age, ethnicity, and sex. Serum tocopherol levels were measured by high performance liquid chromatography. Conditional logistic regression was used to estimate associations between radiographic knee osteoarthritis and tertiles of each tocopherol measure, independent of confounders. Persons in the highest tertile of the alpha:gamma-tocopherol ratio had half the odds of radiographic knee osteoarthritis as those in the lowest tertile (adjusted odds ratio = 0.5, 95% confidence interval: 0.2, 1.2). This inverse association occurred in all ethnic and sex subgroups, significantly in African Americans and men. Radiographic knee osteoarthritis was inversely associated with serum alpha-tocopherol in African Americans and men, positively associated with serum gamma-tocopherol in men, and unassociated with serum delta-tocopherol. Associations between radiographic knee osteoarthritis and tocopherol isoforms are complex and may vary by ethnicity and sex.