Correction of anemia with erythropoietin (EPO) is associated with improved kidney transplant outcomes. Emerging evidence， predominantly from animal models， indicates that these observations may be erythropoiesis-independent and that EPO exhibits immunosuppressive properties. We examined the effects of EPO on human T-cell alloimmunity by first documenting that CD4(+) and CD8(+) T cells express EPO receptor (EPO-R) on their surfaces. In mixed lymphocyte reactions， EPO induced a dose-dependent decrease in allogeneic CD4(+) T-cell proliferation (EPO 1000 U/ml: 44.6%±22.9% of vehicle， P<0.05; 2000 U/ml: 11.1%±4% of vehicle， P<0.001) without inducing cell death. The effects required signals transmitted directly through the EPO-R expressed on T cells， resulting in diminished Th1 differentiation without effects on regulatory T-cell induction. Mechanistic studies revealed that EPO prevented IL-2-induced proliferation by uncoupling IL-2 receptor signaling， inhibiting phosphorylation of the intracellular intermediaries AKT and extracellular signal-regulated kinase that are known to mediate T-cell expansion. EPO treatment reduced expansion of human naïve CD4(+) T cells after adoptive transfer into NOD scid γc(null) mouse recipients， verifying the effects in vivo. Although activated T cells expressed CD131， an alternative EPO receptor， addition of a specific CD131 agonist peptide， ARA290， did not alter T-cell proliferation or cytokine production. Our findings link EPO-R signaling on T cells to inhibition of T-cell immunity， providing one mechanism that could explain the observed protective effects of EPO in kidney transplant recipients.