Background: Endothelial progenitor cells (EPCs) contribute to the maintenance of vascular endothelial function. The moderate consumption of red wine provides cardiovascular protection. Objective: We investigated the underlying molecular mechanism of EPC migration in young, healthy individuals who drank red wine. Design: Fourteen healthy volunteers consumed 250 mL red wine daily for 21 consecutive days. Vascular endothelial function, plasma stromal cell-derived factor 1α (SDF1α) concentrations, and the number, migration, and nitric oxide production of EPCs were determined before and after the daily consumption of red wine. EPCs were glucose stressed to study the effect of red wine on EPC migration, proliferation, and senescence and to study the expressions of CXC chemokine receptor 4 (CXCR4) and members of the Pi3K/ Akt/eNOS (phosphatidylinositol 3-kinase/protein kinase B/endothelial nitric oxide synthase) signaling pathway by Western blotting. Results: Daily red wine consumption for 21 consecutive days significantly enhanced vascular endothelial function. Although plasma SDF1α concentrations were unchanged, EPC count and migration were significantly increased after this 21-d consumption period. Red wine increased the migration, proliferation, CXCR4 expression, and activity of the Pi3K/Akt/eNOS signaling pathway and decreased the extent of apoptosis in glucose-stressed EPCs. Conclusions: The results of the present study indicate that red wine exerts its effect through the up-regulation of CXCR4 expression and activation of the SDF1α/CXCR4/Pi3K/Akt/eNOS signaling pathway, which results in increased EPC migration and proliferation and decreased extent of apoptosis. Our findings suggest that these effects could be linked to the mechanism of cardiovascular protection that is associated with the regular consumption of red wine.