Oxidation of human low-density lipoprotein (LDL) is implicated as an initiator of atherosclerosis. a-Tocopherol (a-TocH) may thus inhibit atherosclerosis because it is the major and most active chain-breaking antioxidant in extracted LDL lipid. Our studies show, however, that a-TocH can be a strong prooxidantfor the LDL itself, ie, an aqueous dispersion of lipid-bearingparticles. Thus, a steady flux (/? e) of alkylperoxylradicals (ROO*) generated from a water-soluble azo initiator induced lipid peroxidation in LDL which was faster inthe presence of a-TocH than in its absence (for Rt< 2 nM s_1), insensitive to R% and [Oi], and inhibited by vitamin C, ubiquinol-10 (normally present in fresh LDL), and small phenolicantioxidants but not inhibited by theaqueous radical scavenger uric acid. Furthermore, LDL peroxidation induced by a water-or lipid-soluble azo initiator or by transition metals in Ham’s F-10 cell culture medium was accelerated by increasing the concentration ofa-TocH in LDL. We propose that LDL peroxidation is initiated by the reaction of ROO* with a-TocH and that the inability of the a-Toc* formed in this reaction to escape from an LDL particle then forces a-Toc* to propagate a radical chain via its reaction with PUFA lipid (LH) within the particle (a-Toc*+ LH+ O2-* a-TocH+ LOO*). Termination of a radical chain occurs when a peroxidizing LDL particle captures a second radical from the aqueous medium (ROO*+ a-Toc*— nonradical products). Steadystate kinetic analysis of this mechanism yields a theoretical model for tocopherol-mediated peroxidation (TMP) in lipid dispersions which fully explains our findings for LDL. We conclude that peroxidation of LDL lipid can (only) be prevented by agents which eliminate the a-Toc* radical: vitamin Cand LDL-associated ubiquinol-10 do so by “exporting the radical" into the aqueous medium, whereas small phenolicantioxidants (eg, butylated hydroxytoluene) accelerate the transfer of radicals between particles. The theoretical and practical implications ofTMP in LDL, dispersions, and bulk lipids are discussed.