Vitamin E uptake after supplementation varies widely in the healthy population, and preliminary studies have indicated that individual responses are relatively stable over periods in excess of 1 year. This phenotypic stability suggests a genetic basis to this observed variation. To examine this issue further, we examined the repeatability of both baseline plasma alpha-tocopherol and urinary alpha-tocopherol metabolite concentrations, as well as individual responses of these parameters after vitamin E supplementation. In the first study, 65 subjects (33 males, 32 females, aged 30.7 +/- 7.4 years) provided three plasma and urine samples for alpha-tocopherol and metabolite analysis with each collection separated by at least 2 weeks. Plasma alpha-tocopherol concentrations were found to be highly repeatable over this short interval (intra-class correlation coefficient [ICC] = 0.85), although the association deteriorated once values were corrected for plasma cholesterol (ICC = 0.64). Similarly, urinary alpha-tocopherol metabolites 2(2'-carboxyethyl)-6-hydroxychroman acid (alpha-CEHC) and quinone lactone (QL) concentration were found to display a moderate degree of intra-subject repeatability: ICC = 0.65 and 0.58, respectively. In a second study, plasma alpha-tocopherol and urinary metabolite responses were investigated in 18 healthy, nonsmoking subjects (12 males, 6 females, aged 33.1 +/- 9.1 years) after successive 6-week periods of vitamin E (RRR-alpha-tocopherol acetate) supplementation at 15, 100, 200, and 400 mg/day. Plasma and urine samples were obtained on days 0, 7, 14, 21, and 28 (7 days after the final supplement) of each dosing period and the strength of the underlying association between responses determined using Kendall's tau_b test. Individual plasma alpha-tocopherol responses at the 100, 200, and 400 mg/day doses were found to be highly associated: tau, 0.51, P = 0.02 [100 vs. 200] and tau, 0.49, P = 0.03 [100 vs. 400] and tau, 0.56, P = 0.005 [200 vs. 400]. Together these data support the contention that alpha-tocopherol uptake is a stable individual phenotype under genetic regulation.