Previous studies comparing the biokinetics of deuterated natural (RRR) and synthetic (all-rac) alpha-tocopherol (vitamin E) used a simultaneous ingestion or competitive uptake approach and reported relative bioavailability ratios close to 2:1, higher than the accepted biopotency ratio of 1.36:1. The aim of the current study was to compare the biokinetics of deuterated natural and synthetic vitamin E using a noncompetitive uptake model both before and after vitamin E supplementation in a distinct population. Healthy men (n = 10) carrying the apolipoprotein (apo)E4 genotype completed a randomized crossover study, comprised of two 4-wk treatments with 400 mg/d (RRR-alpha-tocopheryl and all-rac-alpha-tocopheryl acetate) with a 12-wk washout period between treatments. Before and after each treatment period, the subjects consumed a capsule containing 150 mg deuterated alpha-tocopheryl acetate in either the RRR or all-rac form depending on their treatment regimen. Blood was obtained up to 48 h after ingestion, and tocopherols analyzed by LC/MS. After deuterated all-rac administration, plasma deuterated tocopherol maximum concentrations and area under the concentration vs. time curves (AUC) were lower than those following RRR administration. The RRR:all-rac ratios determined from the deuterated biokinetic profiles (maximum concentration; C(max)) and AUCs were 1.35:1 +/- 0.17 and 1.33:1 +/- 0.18, respectively. The 4-wk supplementation with either RRR or all-rac significantly increased plasma alpha-tocopherol concentrations (P < 0.001), but decreased the plasma response to newly absorbed deuterated RRR or all-rac alpha-tocopherol. Using a noncompetitive uptake approach, the relative bioavailability of natural to synthetic vitamin E in apoE4 males was close to the currently accepted biopotency ratio of 1.36:1.