Vascular dysfunction is one of the major complications in diabetes mellitus. The extended interaction of proteins with aldoses results in non enzymatic glycation, ultimately leading to formation of Advanced Glycation End products (AGE). We showed that increased adhesion of diabetic RBCs was statistically correlated with the vascular severity and glycated hemoglobin level (N. Engl. J. Med., 305:237-242, 1981). We demonstrated that diabetic RBCs bear cell surface AGE which enhance their binding to endothelial cells (EC) and accelerate their clearance via the receptor for AGE (RAGE). Binding of RBCs to EC resulted in oxidant stress based on generation of thiobarbituric acid reactive substances (TBARS) and activation of the transcription factor NFkB, both of which were prevented by preincubation of EC with anti-RAGE IgG or the antioxidant probucol (Proc. Natl. Acad. Sci., 91: 7742-7746, 1994). Incubation of diabetic RBCs with EC increased the diffusional transit of 125I albumin, an effect prevented by preincubation of EC with anti RAGE IgG. Infusion of diabetic rat RBCs in normal rats resulted in oxidant stress and increase in vascular permeability (2 fold elevation). Diabetic RBCs induced generation of TBARS and increased permeability were blocked by anti RAGE or probucol. These data indicate that the interaction of diabetic RBCs with vessel results in oxidant stress, one consequence of which is increased vascular permeability.