Angiogenesis requires the mobilization of progenitor cells from the bone marrow and homing of progenitor cells to ischemic tissue. Statins facilitate the former, and the chemokine stromal cell-derived factor-1 (SDF-1) enhances the latter. Their combined influence on angiogenesis was studied in vivo in the ischemic hindlimb C57BL/6 mouse model. The ischemic to non-ischemic perfusion ratio increased from 0.29 +/- 0.02 immediately after femoral excision to 0.51 +/- 0.10 three weeks after the surgery in the mice treated with either fluvastatin or SDF-1 alone, which is significantly better than the control (0.38 +/- 0.05, p < .05, n = 6). The combined use of fluvastatin and SDF-1 further improved the reperfusion ratio (0.62 +/- 0.08, p < .05). More cell proliferation, less apoptosis, enhanced bone marrow-derived endothelial progenitor cell (EPC) incorporation and higher capillary density were observed in ischemic tissue treated with both statin and SDF-1. In vitro mono-treatment with either fluvastatin (100 nM) or SDF-1 (100 ng/ml) facilitated EPC proliferation and migration, inhibited EPC apoptosis, enhanced expression of matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9), and increased Akt phosphorylation and nitric oxide production. These effects were significantly augmented by the two agents together and ablated by inhibitors of either Akt or nitric oxide synthase (NOS). In conclusion, statin and SDF-1 additively enhance progenitor cell migration and proliferation and down-regulate EPC apoptosis, resulting in improved reperfusion via activation of the Akt/NOS pathway and up-regulation of MMP-2 and MMP-9 expression.