Introduction: Endothelial progenitor cells (EPCs) home to regions of ischemia where they participate in neovascularization. We have previously shown in-vitro that human EPCs harvested from type II diabetics exhibit impaired proliferation, adhesion, and migration following hypoxic insult. Here, we demonstrate that the induction of diabetes in genetically identical animals is sufficient to impair the mobilization and recruitment of EPCs to ischemic tissue in-vivo. Methods: Diabetes was induced in C57BL6 mice with streptazotocin (STZ). Random pattern skin flaps elevated on the dorsum of mice generated a reproducible ischemic gradient. Peripheral blood was analyzed by flow cytometry for EPC mobilization (flk-1+/CD11b-) on day 7. Using an identical flap model on tie2/lacZ bone marrow transplanted mice made diabetic with STZ we studied EPC recruitment via immunohistochemistry. As a human correlate, EPCs isolated from the peripheral blood of normal and Type II diabetics were DiI labeled and injected systemically into athymic nude mice undergoing an ischemic insult. Recruitment and vascular incorporation were assessed via immunohistochemistry. Results: Diabetic mice exhibited a significant impairment in ischemia-induced mobilization of EPCs (% diabetic EPCs vs.% control EPCs; 3.65% vs.12.4%). EPC recruitment to ischemic tissue was also significantly impaired (day 7, diabetic cells vs. control: 34±5 vs. 20±3 cells/HPF). Human EPCs from type-II diabetics exhibited defects in both recruitment to ischemic tissue (day 7, DiI diabetic cells vs. normal: 4±1 vs. 14±3 cells/HPF) and incorporation into new vascular structures. Conclusions: Here, we demonstrate that diabetes impairs ischemia-induced mobilization and tissue recruitment in a murine model. The failure of human diabetic EPCs to localize and incorporate confirms an inherent defect in cell function. These impairments may underlie the poor clinical outcome of type II diabetics following ischemic events and be used as a surrogate marker for cardiovascular risk.