Endothelial progenitor cells (EPC) are considered powerful biologic markers for vascular function and cardiovascular risk, predicting events and death from cardiovascular causes. Colony-forming units of endothelial progenitor cells (CFU-EC) are used to quantify EPC circulating in human peripheral blood. The mechanisms underlying colony formation and the nature of the contributing cells are not clear. We performed subtractive CFU-EC analyses to determine the impact of various blood cell types and kinetics of protein and gene expression during colony formation. We found that CFU-EC mainly comprise T cells and monocytes admixed with B cells and natural killer cells. The combination of purified T cells and monocytes formed CFU-EC structures. The lack of colonies after depletion or functional ablation of T cells or monocytes was contrasted with effective CFU-EC formation in the absence of CD34+ cells. Microarray analyses revealed activation of immune function-related biological processes without changes in angiogenesis-related processes during colony formation. In concordance with a regenerative function, soluble factors derived from CFU-EC cultures supported vascular network formation in vitro. Recognizing CFU-EC formation as the result of a functional cross between T cells and monocytes shifts expectations of vascular regenerative medicine. Our data support the move from a view of circulating EPC toward models that include a role for immune cells in vascular regeneration. Disclosure of potential conflicts of interest is found at the end of this article.