Previous studies have demonstrated that compared with more buoyant LDL, dense LDL (D-LDL) is more susceptible to oxidation and less readily protected from oxidation by antioxidant enrichment. However, diets enriched in monounsaturated fatty acids (MUFAs) appear particularly effective in protecting D-LDL from oxidation. We therefore evaluated in 12 non-insulin-dependent diabetes mellitus subjects the effects of supplementation with alpha-tocopherol (1600 IU/d) and probucol (1 g/d) alone and in combination with an MUFA-enriched diet on LDL and LDL subfraction susceptibility to oxidation and monocyte release of superoxide anion. Subjects received either alpha-tocopherol or probucol for 4 months, and during the fourth month both groups also received an MUFA-enriched diet. alpha-Tocopherol levels were significantly increased in LDL and LDL subfractions (P < .05) after 3 months of supplementation. MUFA-enriched diets led to further increases in alpha-tocopherol in LDL fractions in the alpha-tocopherol group as well as in those receiving probucol. In the alpha-tocopherol-supplemented group, lag times were increased significantly (1.6- to 2.0-fold) for all LDL fractions, although the absolute increase was least for D-LDL. Although probucol supplementation increased lag times of LDL and LDL subfractions three- to fourfold, D-LDL was still more readily oxidized. In both the alpha-tocopherol- and probucol-supplemented groups the benefit of adding MUFA-enriched diets was greatest for D-LDL, with further increases in lag time of 26% and 18%, respectively. Neither antioxidant supplementation nor the addition of an MUFA-enriched diet reduced unstimulated or phorbol ester-stimulated monocyte superoxide anion production. These data demonstrate the markedly different effects that antioxidants and diet may have on different LDL subfractions, which may be particularly important in individuals with non-insulin-dependent diabetes mellitus, who frequently have increased amounts of D-LDL.