Monocyte chemoattractant protein-1 (MCP-1) is a 76-amino-acid chemokine thought to be the major chemotactic factor for monocytes. MCP-1 is found in macrophage-rich areas of atherosclerotic lesions. Recent report indicates that MCP-1 is induced by glucose-stimulation, raising the important link between diabetes mellitus and atherosclerosis. One of the rare sugars, d-psicose (d-ribo-2-hexulose) is present in small quantities in commercial carbohydrate complexes, however the physiological functions of d-psicose have not been evaluated. In this study, we examined the effects of d-psicose on MCP-1 expression in human umbilical vein endothelial cells (HUVECs). Results showed that MCP-1 mRNA and protein were stimulated following exposure to 22.4 mM glucose. Transcriptional activity of MCP-1 promoter paralleled endogenous expression of the gene and this activity was dependent on the dose of d-glucose. d-Psicose inhibited these effects. Next we used inhibitors of selected signal transduction pathways to show that high-glucose (HG) stimulated MCP-1 promoter activity was sensitive to p38-Mitogen-Activated Protein Kinase (p38-MAPK) pathway inhibitor. As expected, a dominant-negative p38-MAPK abolished the stimulatory effect of HG on the promoter activity. To incubate the cells with HG and d-psicose reduced the activation of p38-MAPK. Together, these results indicate that the d-psicose suppression of HG induced MCP-1 expression is mediated in part by inhibition of the p38-MAPK pathway and raise the possibility that d-psicose may be of therapeutic value in the treatment of diseases such as atherosclerosis.