Monocyte Chemoattractant Protein-1 (MCP-1) is involved in the diapedesis of blood monocytes into the arterial intima, an early critical event in atherogenesis. Modulating MCP-1 expression can be a key strategy to decrease the risk for atherosclerosis in diabetes. We hypothesized that quercetin, an anti-inflammatory molecule could modulate high glucose concentration (HG) induced MCP-1 expression in aortic endothelial cells in vitro because of its regulatory effects on Activator Protein-1 (AP-1) and Nuclear Factor-κB (NF-κB). Rat aortic endothelial cells (RAECs) were exposed to HG in the presence or absence of quercetin. Quercetin attenuated HG induced MCP-1 mRNA (42%) and protein synthesis (45%) when estimated using real-time reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay respectively. Western blot analysis found quercetin to maintain cytosolic p65 protein levels to that seen in control. Quercetin was found to attenuate HG induced increased NF-κB and AP-1 DNA binding activity in electrophoretic mobility shift assay. Immunofluorescence studies revealed quercetin to prevent HG induced nuclear localization of p65 and c-jun. Quercetin was also found to decrease HG induced activation of NF-κB (71% ± 14%), AP-1 (69% ± 24%) and MCP-1 promoter (79% ± 25%) in EA.hy926 cells when analyzed using luciferase reporter assay.We conclude that quercetin attenuates MCP-1 expression in HG treated RAECs, probably by regulating both NF-κB and AP-1 pathways. The findings provide new insights into HG induced MCP-1 gene regulation in aortic endothelial cells and the potential of quercetin in abating the risk for atherosclerosis in diabetes. © 2010 Elsevier Ltd.