This report describes the effects of feeding linoleate- or oleate-enriched diets to subjects who were concurrently taking 1200 mg/d of alpha-tocopherol on the susceptibility of low-density lipoprotein (LDL) and buoyant and dense LDL subfractions to oxidation. LDL isolated from subjects who consumed linoleate-enriched diets was more susceptible to copper-mediated oxidation, as measured by formation of conjugated dienes and lipid peroxides and loss of unsaturated fatty acids, compared with LDL isolated from subjects who consumed their usual or oleate-enriched diets. In all subjects, buoyant LDL had a higher content of alpha-tocopherol per particle and a lower 18:2 to 18:1 ratio and was considerably more resistant to oxidation than dense LDL. Although dense LDL from all groups had comparable alpha-tocopherol levels, dense LDL from the linoleate group was most susceptible to oxidation, followed by that from the standard diet, whereas dense LDL isolated from the oleate diet group was most resistant. In summary, high dosages of alpha-tocopherol did not prevent enhanced susceptibility to oxidation of LDL isolated from subjects fed linoleate-enriched diets. Furthermore, dense LDL was more susceptible to oxidation than was buoyant LDL, and this effect was greatly exaggerated in the dense LDL isolated from subjects fed linoleate-enriched diets. Conversely, dense LDL isolated from subjects fed oleate-enriched diets was the most protected. If oxidation of LDL is important in the pathogenesis of atherosclerosis, then these data suggest that in people with increased amounts of small, dense LDL, dietary enrichment in oleic acid may decrease the susceptibility of their LDL to oxidation.