Circulating endothelial progenitor cells (cEPCs) home from the bone marrow to the site of tissue regeneration and sustain neo-vascularization after acute vascular injury and upon the angiogenic switch in solid tumors. Therefore, they represent a suitable tool for cell-based therapy in regenerative medicine and provide a novel promising target in the fight against cancer. Intracellular Ca²⁺signals regulate numerous endothelial functions, such as proliferation and migration. We have recently shown that EPC growth is governed by a store-dependent Ca²⁺entry (SOCE) pathway. The present study aimed at investigating VEGF-elicited Ca²⁺signals in cEPCs and in cord blood-derived EPCs (CB-EPCs). All the putative SOCE mediators (i.e. TRPC1, TRPC4, Orai1 and Stim1) were present in both EPC types, while the DAG-sensitive channel TRPC3 was expressed only in CB-EPCs. VEGF induced long lasting Ca²⁺oscillations in cEPCs, however, removal of external Ca²⁺(0Ca²⁺) and SOCE inhibition with BTP-2 reduced the number of spikes. Blockade of PLC with U73122 and emptying the IP₃-sensitive Ca²⁺pools with CPA prevented the Ca²⁺response. Thus, VEGF cause an initial IP₃-dependent Ca²⁺discharge followed by SOCE-mediated Ca²⁺entry in cEPCs. Conversely, Ca²⁺spiking did not occur under 0Ca²⁺in CB-EPCs, but was blocked by U73122, CPA and BTP2. Notably, OAG induced a similar pattern of Ca²⁺oscillations in CB-EPCs. Thus, the trigger of the Ca²⁺response to VEGF is different in the two cell types.