Background Fibroblast growth factor-2 (FGF2) regulates proliferation of bone marrow (BM) stromal cells and has pro-angiogenic effects regulating endothelial cell growth, migration, and reendothelialization. We have previously demonstrated that estrogen-mediated endothelial progenitor cell (EPC) mobilization from BM into peripheral blood is inhibited in FGF2 knock-out (−/−) mice indicating a central role of medullary FGF2 in progenitor cell mobilization. Here we determine the underlying molecular mechanisms of FGF2-dependent statin-mediated progenitor cell mobilization. Methods and Results To determine the molecular mechanisms of FGF2-mediated progenitor cell mobilization, FGF2−/− and wild type (wt) mice were treated with the HMG-CoA reductase-inhibitor rosuvastatin (10mg/kg body weight s.c. per day) and placebo. In contrast to wt mice, the number of Sca1/flk-1 positive EPC in peripheral blood of rosuvastatin treated FGF2−/− mice did not increase. This was due to an accumulation of Sca1/flk-1 positive cells within the BM. Inhibition of EPC mobilization in FGF2−/− mice was associated with a delay in reendothelialization in a mouse model of focal endothelial cell denudation and a severe reduction in neoangiogenesis despite statin treatment. BM transplantation experiments demonstrated that reconstitution of FGF2−/− mice with wt stem cells completely restored statin-mediated EPC mobilization while wt mice reconstituted with FGF2−/− stem cells developed a mobilization defect associated with an impaired endothelial-dependent vasore-laxation and enhanced neointima formation. In wt mice, statin treatment was associated with an increased number of activated osteoclasts compared to placebo treated mice which are known to play a pivotal role in stem cell mobilization. Conclusion Medullary FGF2 is essential in the statin-mediated mobilization of EPC from BM into peripheral blood while it seems not to influence EPC proliferation. The mobilization defect in FGF2−/− mice is associated with a significant impairment of vascular endothelial function and repair which underlines the importance of EPC in endothelial cell regeneration.