Backgrounds: Advanced glycation endproducts (AGEs) accumulation in a high glucose environment is thought to enhance the local oxidant stress and immunoinflammatory reaction and mediate some of vascular complications of diabetes. AGEs also have been reported to play a role in neointimal formation in the animal model of arterial injury. However, the role of AGE in vascular smooth muscle cell (VSMC) proliferation remains unclear. We sought to determine the potential role of AGEs in the VSMC proliferation and associated increased atherosclerosis in diabetes. Methods & Results: We evaluated whether the high serum levels of AGEs were associated with in-stent restenosis (ISR) of diabetic PCI patients. Activation of VSMC proliferation by AGE is associated with mitogen-associated protein kinase (MAPK) system, an important signaling pathway associated with VSMC proliferation. Blood samples were collected from the diabetic CAD patients and the serum levels of AGEs were analyzed by the fluorescent intensity method. Rat aortic smooth muscle cell culture was done using the different levels of AGEs stimulation. Western blotting was performed to assess the activation of MAPK system in the cultured VSMC. Flow cytometric analysis was performed on a FACSCalibur system using anti-SERCA and PKC rabbit antibody. Increasing concentration of AGEs was associated with increased VSMC proliferation and was associated with increased phosphorylation of ERK, JUN, and p-38. Increased reactive oxygen species (ROS) formation by AGEs influence the intracellular calcium homeostasis. The expression of RAGE in human atheroma was assessed by immunohistochemistry. AGE inhibitor, Aminoguanidine, significantly inhibited activation of ERK and the formation of ROS. Conclusions: High serum levels of AGEs increase ISR in diabetes. In vitro data suggest that AGEs may play a key role in VSMC proliferation and increase the oxidative stress. Activation of MAPK system and increased formation of ROS may be the possible mechanism of AGEs induced diabetic vasculopathy.