<p>The mechanism of anemia in patients with end-stage renal disease (ESRD) and its association with poor prognoses (including cardiovascular disease and mortality) are unclear. We investigated the role of CD71⁺ erythroid progenitor cells (EPCs), which are associated with compensatory extramedullary hematopoiesis in anemia and cancers, in patients and mice with ESRD. Circulatory CD45⁻EPCs (CD45⁻CD71⁺CD235a⁺) were elevated in patients with ESRD and 5/6th partial nephrectomy (PNx) mice compared with those in healthy controls. CD45⁺EPCs (CD45⁺CD71⁺CD235a⁺) in peripheral blood mononuclear cells (PBMCs) were elevated in patients with ESRD. CD45⁺EPCs were positively associated with hemoglobin levels, whereas CD45⁻EPCs were negatively associated. Wright–Giemsa staining revealed that the majority of CD45⁻EPCs were mainly anucleated red blood cells, many of which were ruptured, and CD45⁺EPCs exhibited multiple stages of erythroblasts and ruptured cells. Single-cell RNA sequencing of CD45⁺EPCs revealed that CD45⁺ EPC population exhibits a mixed transcriptional signature with features of both erythroid and myeloid lineages. CD45⁺EPCs in patients with ESRD exhibited increased myeloid cell surface markers, decreased maturation potential, as well as mitochondrial retention and dysfunction. CD71⁺EPCs in PNx mice promoted tumor metastasis associated with platelets. Pathological analysis and immunofluorescence revealed that CD71⁺EPC were mainly located in the arterial subintima, and their abundance was positively associated with the pathological grading of atherosclerosis. Kaplan–Meier and multivariate Cox analyses revealed that patients with high levels of CD45⁻EPCs presented an increased incidence of stroke. Overall, accumulation of CD71⁺EPCs were invalid extramedullary hematopoiesis compensation in ESRD and mediates anemia-related poor prognoses.</p>