BACKGROUND: Clinical studies of the associations of vitamin E with lung function have reported conflicting results. However, these reports primarily examine the alpha-tocopherol isoform of vitamin E and have not included the isoform gamma-tocopherol which we recently demonstrated in vitro opposes the function of alpha-tocopherol. We previously demonstrated, in vitro and in animal studies, that the vitamin E isoform alpha-tocopherol protects, but the isoform gamma-tocopherol promotes lung inflammation and airway hyperresponsiveness. METHODS: To translate these findings to humans, we conducted analysis of 4526 adults in the Coronary Artery Risk Development in Young Adults (CARDIA) multi-center cohort with available spirometry and tocopherol data in blacks and whites. Spirometry was obtained at years 0, 5, 10, and 20 and serum tocopherol was from years 0, 7 and 15 of CARDIA. RESULTS: In cross-sectional regression analysis at year 0, higher gamma-tocopherol associated with lower FEV1 (p = 0.03 in blacks and p = 0.01 in all participants) and FVC (p = 0.01 in blacks, p = 0.05 in whites, and p = 0.005 in all participants), whereas higher alpha-tocopherol associated with higher FVC (p = 0.04 in blacks and whites and p = 0.01 in all participants). In the lowest quartile of alpha-tocopherol, higher gamma-tocopherol associated with a lower FEV1 (p = 0.05 in blacks and p = 0.02 in all participants). In contrast, in the lowest quartile of gamma-tocopherol, higher alpha-tocopherol associated with a higher FEV1 (p = 0.03) in blacks. Serum gamma-tocopherol >10 muM was associated with a 175-545 ml lower FEV1 and FVC at ages 21-55 years. CONCLUSION: Increasing serum concentrations of gamma-tocopherol were associated with lower FEV1 or FVC, whereas increasing serum concentrations of alpha-tocopherol was associated with higher FEV1 or FVC. Based on the prevalence of serum gamma-tocopherol >10 muM in adults in CARDIA and the adult U.S. population in the 2011 census, we expect that the lower FEV1 and FVC at these concentrations of serum gamma-tocopherol occur in up to 4.5 million adults in the population.