Background Both the number and function of bone marrow-derived endothelial progenitor cells (EPCs) have been shown to be impaired in patients with diabetes mellitus. Therefore, we investigated the effect of glucose on the senescence of EPCs. Methods and Results EPCs were isolated from human peripheral blood and characterized to evaluate the effect of glucose (in 5-12.5 mmol/L) on the rate of senescence by acidic β-galactosidase staining. The phosphorylation of p38 mitogen-activated protein kinase (MAPK) level was analyzed by ELISA. The exposure of cultured EPC to high glucose (HG; 12.5 mmol/L) significantly accelerated the rate of senescence compared with that in osmolar control (L-glucose) during 10 days culture. An inhibitory effect of HG on EPC proliferation disclosed by an MTS assay. The phosphorylation of p38 MAPK in EPCs was also increased by glucose compared with control in a dose-dependent manner. HG-induced EPC senescence was significantly inhibited by the addition of an inhibitor of the p38 MAPK, SB203580. Conclusions HG accelerates the onset of EPCs senescence leading to the impairment of proliferative activity, which might be related to the phosphorylation of p38 MAPK. (Circ J 2006; 70: 1076 - 1081)