Much of the oxidative damage to human LDL in vivo may lead to only minimal changes in the chemical properties of the LDL. Therefore, chemical changes were evaluated during the initial 3 hours of oxidative attack on human LDL with 5 microM Cu. HPLC analyses were calibrated with a conjugated-diene internal standard. Cholesterol-linoleate-hydroperoxide (Chol-18:2-OOH) accumulated much more rapidly than alpha-tocopherol was lost. Although large amounts of cholesterol arachidonate were destroyed, diene-containing oxidation products of this lipid were not identified by HPLC analysis. Phosphatidyl-choline-hydroperoxides accumulated much more slowly than chol-18:2-OOH. beta-carotene was oxidized relatively slowly, but lycopene was destroyed almost as fast as alpha-tocopherol. The preferential accumulation of chol-18:2-OOH is consistent with a model in which alpha-tocopherol is localized to the surface of the LDL particle, providing minimal protection to hydrophobic components in the core of the LDL.