Studies from several laboratories suggest that oxidized LDL may play an important role in atherogenesis. Our group previously showed that treatment of aortic endothelial cells with low levels of MM-LDL caused increased expression of MCP-1, M-CSF, tissue factor, and a monocyte-binding protein. In these studies MM-LDL was produced by storage of native LDL. We now show that cocultures of endothelial and smooth muscle cells can also produce MM-LDL from native LDL. This production of MM-LDL by cells is prevented by preincubating the LDL with probucol or vitamin E. However, addition of antioxidants to MM-LDL did not block its action. In past studies we also showed that endothelial cells exhibit differential sensitivity to the effects of MM-LDL. We report herein that in resistant cells there is no elevation of catalase, glutathione peroxidase, or copper-zinc-dependent SOD. However, manganese-dependent SOD is elevated in resistant cells. Ways in which MM-LDL production may be elevated in poorly controlled diabetics subjects are discussed.