Background-RAGE (receptor for advanced glycation end products [AGEs]) plays a role in diabetic atherosclerosis.Recently, we have demonstrated enhanced expression of cyclooxygenase-2 and PGE synthase-1 (COX-2/mPGES-1) in human symptomatic plaques, and provided evidence that it is associated with metalloproteinase (MMP)-induced plaque rupture. However, the specific transmembrane signaling pathway(s) influencing plaque COX-2/mPGES-1 expression is unknown. The aim of this study was to characterize RAGE expression in human plaques and to correlate it with the inflammatory infiltration, COX-2/mPGES-1 and MMP expression, and with clinical evidence of diabetes. Methods and Results-Plaques obtained from 60 patients undergoing carotid endarterectomy were divided into diabetic and nondiabetic according to clinical evidence of type 2 diabetes. Plaques were subjected to analysis of RAGE, NF-B, COX-2/mPGES-1, MMP-2 and MMP-9, lipid and oxidized LDL (oxLDL) content, and collagen content by immunohistochemistry and Western blot, whereas zymography was used to detect MMP activity. Immunohistochemistry was used to identify CD68ϩ macrophages, CD3ϩ T-lymphocytes, smooth muscle cells (SMCs), and HLA-DRϩ inflammatory cells. Diabetic plaques had more (PϽ0.0001) macrophages, T-lymphocytes, and HLA-DRϩ cells, more (PϽ0.0001) immunoreactivity for RAGE, activated NF-B, COX-2/mPGES-1, and MMPs, increased (PϽ0.0001) gelatinolytic activity, reduced (PϽ0.0001) collagen content, and increased (PϽ0.0001) lipid and oxLDL content. Interestingly, RAGE, COX-2/mPGES-1, and MMP expression was linearly correlated with plasma level of HbA1c. Conclusions-In conclusion, this study demonstrates in humans that RAGE overexpression is associated with enhanced inflammatory reaction and COX-2/mPGES-1 expression in diabetic plaque macrophages, and this effect may contribute to plaque destabilization by inducing culprit metalloproteinase expression.