Limited information is available on factors that can influence vitamin E bioavailability. In several studies we have investigated the influence of dietary, biochemical, and genetic factors on vitamin E biokinetics. In these studies, subjects ingested a capsule containing 150 mg deuterated RRR-alpha-tocopheryl acetate, blood was taken up to 48 hr, and tocopherols were analyzed by liquid chromatography and mass spectroscopy. There was significantly greater plasma-labeled alpha-tocopherol concentrations when the capsule was consumed with a high-fat meal (17.5 g) versus a low-fat meal (2.7 g), and there was also a difference between a high-fat toast and butter and a cereal with full-fat milk meal (both 17.5 g fat), indicating that both the amount of fat and food matrix is important for vitamin E absorption. Dyslipidemic subjects displayed a reduced plasma uptake of newly absorbed alpha-tocopherol, and differences were also apparent in individual lipoproteins. A decreased uptake of labeled alpha-tocopherol was also observed in erythrocytes, platelets, and lymphocytes of dyslipidemics. Following vitamin E supplementation (400 mg/day, 4 weeks), the uptake of newly absorbed alpha-tocopherol was decreased, presumably because of saturation of alpha-tocopherol transfer protein. We also found that apoE3 subjects displayed a considerably reduced uptake of newly absorbed labeled alpha-tocopherol compared to apoE4 subjects, which may be a consequence of the reduced low-density lipoprotein catabolic rate in these subjects. Taken together, these data show that several physiological factors influence the uptake of newly absorbed alpha-tocopherol, and that this is an important consideration in the design of future vitamin E supplementation studies.