Objective: Modulatory effects of erythropoietin (EPO) on the cellular and humoral compartments of the immune system have been described; however, the mechanism of action by which EPO affects the lymphocyte number and functions has yet to be elucidated. Because no EPO receptors (EPO-R) could be detected on lymphocytes, we searched for cells that might express the EPO-R and thereby mediate these immunomodulatory effects. We thus focused on dendritic cells (DCs), the most potent antigen-presenting and T-cell-priming cells, as possible mediators of the immunomodulatory actions of EPO. Materials and Methods: We examined the in vitro effects of EPO on human DCs. Expression of EPO-R, expression of costimulatory molecules, antigen uptake, secretion of cytokines, and DC maturation were investigated. Results: We demonstrate that the EPO-R is expressed in human DCs and that EPO directly affects their phenotype and function. When applied in vitro, EPO increased the percentage of peripheral blood DCs and monocyte-derived DCs (MoDCs) expressing the costimulatory molecules CD80 and CD86. EPO treatment of MoDCs was also associated with an increase in surface expression of CD80 and CD86 as well as that of HLA-DR. EPO enhanced MoDC function, as manifested in increased antigen uptake and secretion of interleukin 12. When applied to immature MoDCs, EPO in itself induced their maturation. Conclusion: Our finding that DCs are directly affected by EPO renders them as potential candidates that mediate the immunomodulatory actions of EPO.