It is important to understand factors that can influence vitamin E bioavailability, particularly in populations with increased risk of coronary heart disease such as cigarette smokers. There is also a need to clarify the bioavailability of natural and synthetic vitamin E, which is currently a subject of some controversy. Previous studies using a competitive uptake approach have found bioavailability ratios of natural:synthetic vitamin E close to 2:1, differing from the accepted biopotency ratio of 1.36:1. We used a non-competitive uptake approach to compare the plasma biokinetics of deuterated natural (RRR) and synthetic (all rac) alpha-tocopheryl acetate in smokers and non-smokers. The study was comprised of two 4-week treatments with 400 mg/d (either RRR-alpha-tocopheryl or all rac-alpha-tocopheryl acetates), with a 12-week washout period between. Prior to and after each treatment subjects underwent a 48 h biokinetic protocol with 150 mg deuterated alpha-tocopheryl acetate in either the RRR or all rac form. Smokers had a lower deuterated alpha-tocopherol AUC than did non-smokers following administration of RRR, but there was no difference following administration of all rac. The ratio RRR:all rac from AUCs and C(max) was 1.3:1 in non-smokers and 0.9:1 in smokers. Following vitamin E supplementation, deuterated tocopherol AUCs were lower in both groups. These data suggest that non-smokers and smokers differ in their handling of vitamin E, that the relative bioavailability of natural and synthetic vitamin E is close to the currently accepted biopotency ratio of 1.36:1, and that following supplementation the ability of the plasma to take up newly absorbed vitamin E is decreased.