In multiple myeloma (MM), circulating endothelial cells (CECs) represent a vascular marker of angiogenesis and may reflect tumor mass. In this report, we showed that, in 5 MM patients with 13q14 deletion, CECs carried the same chromosome aberration as the neoplastic plasma cells (11%-32% of CECs with 13q14 deletion). Most of the CECs displayed immunophenotypic features of endothelial progenitor cells as they expressed CD133, a marker gradually lost during endothelial differentiation and absent on mature endothelial cells. To the contrary, in 3 patients with monoclonal gammopathy of undetermined significance and 13q14 deletion, CECs were cytogenetically normal and had a mature immunophenotype. In MM CECs, immunoglobulin genes were clonally rearranged. These findings suggest a possible origin of CECs from a common hemangioblast precursor that can give rise to both plasma cells and endothelial cells and point to a direct contribution of MM-derived CECs to tumor vasculogenesis and possibly to the spreading and progression of the disease.