BACKGROUND:: Cigarette smoking increases the fractional disappearance rates of α-tocopherol and is associated with increased oxidative stress, but its effects on α-tocopherol metabolism are unknown. OBJECTIVE:: We hypothesized that smokers would have less α-tocopherol available and consequently lower plasma α-carboxyethyl-hydroxychroman (α-CEHC), the α-tocopherol metabolite produced by a cytochrome P450-mediated process. DESIGN:: Smokers and nonsmokers (n = 10 per group) were supplemented with deuterium-labeled α-tocopheryl acetates (75 mg each d3-RRR-α-tocopheryl and d6-all-rac-α-tocopheryl acetate) from day -6 to day -1, and plasma tocopherols and CEHCs were measured (day -6 through day 17). RESULTS:: After 6 d of supplementation, plasma d3- and d6-α-tocopherol concentrations did not differ significantly between groups. Plasma d3- and d6-α-CEHCs were detectable only from day -5 to day 5. Before supplementation, unlabeled α- and γ-CEHCs were ≈60% and 40% lower, respectively, in smokers than in nonsmokers (P ≤ 0.05). In addition, d0-, d3-, and d6-α-CEHC areas under the curves were ≈50% lower in smokers (P < 0.05), and smokers had lower maximal d3-α-CEHC (P = 0.004) and d6-α-CEHC (P = 0.0006) concentrations. Notably, 2.9-4.7 times as much α-CEHC was produced from all-rac-α-tocopherol than from RRR-α-tocopherol. During supplementation, smokers had about one-half (P < 0.05) the plasma total, d6-, or d3-α-CEHC concentrations that nonsmokers did given similar α-tocopherol concentrations. CONCLUSIONS:: Smoking did not increase α-tocopherol disappearance through P450-mediated tocopherol metabolism. Therefore, the mechanism of increased α-tocopherol disappearance in smokers likely operates through oxidation pathways, which is consistent with α-tocopherolʼs antioxidant function. Consequently, evaluating the molecular mechanism or mechanisms responsible for tocopherol metabolism under conditions of oxidative stress and the mechanisms that regulate α-tocopherol status is warranted. Am J Clin Nutr 2005;81:1052-9.