Recombinant human erythropoietin (rHuEpo) is now widely employed in correction of the anemia of end stage renal disease (ESRD). Recent reports suggest that rHUEpo, in addition to its effect on CFU-E and burst-forming-unit-erythroid (BFU-E), may stimulate granulocyte/macro-phage production and pluripotential progenitors of the myeloid and monocyte lineage. Furthermore, there is now data which demonstrate that ESRD patients who received rHuEpo have enhanced cytokine production. Taken together, these observations suggest that the administration of rHuEpo may augment the diminished immune response of renal failure patients. To evaluate the effects of rHuEpo therapy on cell-mediated immunity in hemodialysis patients, a prospective controlled study was conducted. Two parameters of immune function were tested. One was natural killer cell (NK) activity, and the other proliferation in response to the T cell mitogen concanavalin A (Con-A). NK activity of the ESRD patients was comparable with that of normal controls at the start of the study and was unaffected by rHuEpo therapy. In contrast to this, anemic ESRD patients initially demonstrated impaired mitogen driven proliferation (initial stimulation index (S.I.) = 42.5 +/- 11.9) which significantly improved following rHuEpo therapy (final S.I. = 73.3 +/- 14.7, p < 0.05). The later value exceeded the mitogen response in less anemic ESRD patients who did not receive rHuEpo (initial S.I. = 60.7 +/- 16.5, final S.I. = 61.0 +/- 16.7), but did not reach values seen in normal controls. The data suggest that rHuEpo therapy may be associated with enhanced immune responses in patients with ESRD.