Radiation-induced decreases in the number of bone marrow (BM)-derived endothelial progenitor cell (BM-EPCs) and their lineage precursors which include Early- and Late-Multi-Potent Progenitor cells (E-MPP and L-MPP) could contribute to the pathogenesis of ischemic and vascular diseases. We examined the effect of full-body single dose of proton (1H) at 0.5 Gy, 1 GeV and 0.15 Gy, 1 GeV/nucleon of iron (56Fe) - ionizing radiation (IR) on survival and proliferation of BM-EPCs. The survival of E-MPPs and L-MPPs in the BM after particle IR in C57BL/6 mice were determined at 1, 2, 4, 8, 12, 28 and 40 weeks post-IR. BM-derived mononuclear cells were triple-stained with RAM34 (CD34, c-kit, and Sca1), AC133, and hematopoietic lineage negative cocktail, then sorted by FASC for E- and L-MPP. BM EPCs ex-vivo - There was a transient 2.5-3.5-fold increase in BM-EPC apoptosis, with 3.5-fold increases for 56Fe and 1H at 5hrs and 24hrs, respectively that was no longer detected by day 7. Subsequently, there was a 3-fold increase in BM-EPC apoptosis on day 28 for both ion-IR mice. Compared to 24 hrs, there was a ~20% (1H) and ~45% (56Fe) increase in the rate of EPC proliferation on day 14 that returned to control levels on day 28. BM E-MPP and L-MPP in vivo - Compared to control mice, 1H-IR increased the number of both E-MPPs (665%) and L-MPPs (203%), whereas 56Fe-IR decreased E-MPP (74%) and L-MPPs (65%) at 1 week post-IR, suggesting stimulation by 1H but overt damage by 56Fe in the BM milieu. In 56Fe-IR mice, E-MPPs recovered between 4 and 12 weeks, followed by declines at later time points. In 1H-IR mice, E-MPPs were near control levels up to 4 weeks, but declined at later time points. The long-lasting and cyclical effects of IR on the BM E- and L-MPPs after a single 1H or 56Fe IR dose suggests the presence of prolonged and non-targeted effects in BM milieu, that occur in cells that were not traversed by IR, rather induced by signals from IR cells. Our studies showed that, both 1H- and 56Fe-IR has profound and long-lasting (28-40 months) negative effects on the number of E- and L-MPPs. Future longitudinal studies are necessary to determine whether BM progenitor cells may be affected after terrestrial IR exposure, such as cancer radiotherapy, CT and PET scans, and in astronauts after exploration-type space missions.