There is accumulating evidence that oxidative modification of LDL is an important step in the process of atherogenesis and that antioxidants may protect LDL from oxidation. We and others have previously shown that ingestion of pharmacological doses of the antioxidant D,L-α-tocopherol (vitamin E), far above the recommended daily intake (ie, 12 to 15 IU/d for adults), increases the oxidation resistance of LDL. In this study, we ascertained the minimal supplementary dose of vitamin E necessary to protect LDL against oxidation in vitro. Twenty healthy volunteers (10 men and 10 women, aged 21 to 31 years) ingested consecutively 25, 50, 100, 200, 400, and 800 IU/d D,L-α-tocopherol acetate during six 2-week periods. No changes were observed in LDL triglyceride content, fatty acid composition of LDL, or LDL size during the intervention. Concentrations of α-tocopherol in plasma and LDL were both 1.2 times the baseline values after the first period (25 IU/d) and 2.6 and 2.2 times, respectively, after the last period (800 IU/d). There was a linear increase in LDL α-tocopherol levels up to an intake of 800 IU/d (r = .79, P < .0001) and a good correlation between α-tocopherol in plasma and LDL (r = .66, P < .0001). Simultaneously, the resistance of LDL to oxidation was elevated dose-dependently (+28% after the last period) and differed significantly from the baseline resistance time even after ingestion of only 25 IU/d. Correlation between α-tocopherol content of LDL and resistance time for all data was r = .57 (P <.0001), whereas the correlation between plasma α-tocopherol and resistance time was r = .69 (P < .0001). The rate of oxidation was decreased significantly at 400 and 800 IU/d (-13% and -17%, respectively). Baseline resistance time was not significantly different between men and women, but propagation rate was higher with LDL from men at baseline and after intake of 25 and 50 IU/d. Minor differences in LDL vitamin E levels and resistance time were found between men and women in response to vitamin E intake. Statistical evaluation of the relations between α-tocopherol content of LDL and resistance time in each of the 20 individual subjects showed strong and significant correlations for 14 individuals, indicating that vitamin E was the most important parameter that determined the oxidation resistance of LDL in these subjects. ANOVA indicated that LDL α-tocopherol content (47%) and interindividual variation (39%) were the most prominent parameters that contributed to the total variance in resistance time. Chemicals/CAS: alpha tocopherol, 1406-18-4, 1406-70-8, 52225-20-4, 58-95-7, 59-02-9; Ascorbic Acid, 50-81-7; Lipid Peroxides; Lipoproteins, LDL; Vitamin E, 1406-18-4