Oxidative modification of low density lipoprotein (LDL) has been implicated as a factor in the generation of macrophage-derived foam cells in vitro and in vivo. However, the exact mechanism of LDL oxidation has not been established. The present studies show that cellular lipoxygenase activity is involved in endothelial cell-induced oxidation of LDL. Inhibitors of lipoxygenase (but not inhibitors of cyclooxygenase) reduced LDL oxidation by as much as 70-85% under the conditions used. In contrast, the addition of pure (recombinant) superoxide dismutase inhibited by only approximately 25% under the same conditions. Oxidation of LDL by smooth muscle cells, on the other hand, was effectively inhibited by superoxide dismutase, as was Cu2+-catalyzed oxidation of LDL. When LDL was added to endothelial cell cultures within a dialysis bag, it did not undergo oxidative modification, suggesting that cell-LDL contact is necessary. We propose that an important element in cell-induced oxidation of LDL depends on (i) lipoxygenase oxidation of cellular lipids, followed by their exchange into LDL in the medium; (ii) direct lipoxygenase-dependent oxidation of LDL lipids during LDL-cell contact; (iii) or both.