The pleiotropic effects of HMG CoA reductase inhibitors are well-known including regulation of angiogenesis and survival of endothelial progenitor cells (EPCs). However, the effects of statin on EPC differentiation, proangiogenic cytokines, and whether these effects are seen in humans are unknown. Twenty-two lone hypercholesterolemia patients without any other modifiable cardiovascular risk factors and without history of previous lipid lowering therapy were enrolled and given simvastatin (Sv) 20mg/day for 4 weeks. Sv treatment significantly increased the number of DiI-acLDL, UEA-1 lectin double positive EPCs and facilitated its appearance. By FACS analysis of freshly isolated PBMNCs from patients, KDR (+) cells significantly increased after Sv treatment (∆mean from isotype antibody; 1.29 vs. 4.80 for pre- vs. post-statin, p<0.05), while there were no significant differences in CD34, AC133, and VE-cadherin. Also, Sv treatment resulted in a marked increase in serum IL-8 level and a small increase in serum VEGF level. Corroborating these clinical findings, in vitro experiments using PBMNCs from healthy volunteers showed that co-culture with Sv increased cluster formation at day 7 and facilitated the appearance and networking of EPCs compared with vehicle. Also, PBMNCs cultured with Sv compared with vehicle showed significantly increased KDR (+) cells, while no significant shifts were seen in CD34, CD31, and VE-Cadherin (+) cells. Search for the source of IL-8 and VEGF in plasma after statin therapy revealed that IL-8 was mainly derived from monocytes and VEGF from smooth muscle cells. These cytokines were associated with increased EPC migratory function. The increase in IL-8 secretion from monocytes by statin treatment was associated with phosphorylation and inactivation of GSK3棺, which was reversed by constitutive activation of GSK-3棺. In conclusion, Sv enhances endothelial differentiation of peripheral blood mononuclear cells in patients with lone hypercholesterolemia and increases proangiogenic cytokine IL-8 secretion from monocytes. Our results may explain the proangiogenic effects associated with statin therapy and offer further evidence of statin pleiotrophism.