BACKGROUND: One theory of aging and disease development is that chronic injury (pathology) results in activation of regenerative processes and initial repair, with overt disease arising only after exhaustion of reparative capability leads to inadequate repair. While depletion of circulating progenitor cells (CPCs) has been noted in diabetes, the degree to which CPC depletion predates and is associated with propensity to develop overt disease is unclear. METHODS: The Enhanced Fitness trial enrolled overweight/obese (body mass index >25) sedentary patients with glucose intolerance but without overt diabetes. Baseline CPCs were measured in 129 patients based on the cell surface markers CD34, CD133, and aldehyde dehydrogenase (ALDH) activity. HgbA1C, fasting insulin and glucose levels, and HOMA calculations were ascertained. RESULTS: Lower counts of early angiogenic CPCs identified as CD34(+), CD34(+)CD133(+), and ALDH-bright (ALDH(br)) cells were associated with impairments in glucose homeostasis as reflected by HgbA1C, but not fasting insulin, glucose, or HOMA-IR. These associations remained when corrected for age and cardiovascular risk factors. CONCLUSIONS/INTERPRETATION: The numbers of CD34(+) and ALDH(br) CPCs were significantly lower in patients with impaired glucose tolerance. Depletion of reparative capacity as reflected by loss of CPCs may presage overt disease as exemplified in this pre-diabetes model.