Many in vitro studies demonstrate various stimulatory effects of red blood cells (RBC) on T cell reactivity. Only a few suggest a role for RBC in vivo, such as decreased B and T cell function in iron deficiency anemia. Immune deficiency of uremia is only partially corrected by dialysis treatment. We postulated therefore that this anemia may contribute in part to the immune deficiency of uremia. The aim of our study was to evaluate this postulate and to investigate the role RBC may have in the immune system in vivo. The in vitro secretion of interleukin-2 (IL-2), γ-interferon (γ-IFN), tumor necrosis factor (TNF) and colony stimulating factor (CSF) by human peripheral blood mononuclear cells isolated from patients and controls was used as a measure of immune function. The following protocols were carried out: IL-2 secretion was measured in patients with end-stage renal disease (ESRD) and in controls. RBCs were transfused to patients with ESRD and secretion of cytokines was measured before, and 4 hours, 4, 7 and 14 days afterwards; patients with ESRD received recombinant human erythropoietin (rHuEpo) and secretion of cytokines was measured before treatment and two and four months later. Finally, the effect of phlebotomy and transfusion of the autologous blood on cytokine secretion in healthy subjects was measured. Secretion of IL-2 by patients with ESRD was substantially lower than that of healthy subjects. In each group, IL-2 secretion correlated positively with hemoglobin level, r = 0.73, P < 0.01 and r = 0.71, P < 0.01. Following transfusion of RBC, secretion of all cytokines rose at the early stage of the study and stayed elevated throughout the study period. Following treatment with rHuEpo secretion of the four cytokines rose progressively and in parallel to the rise in hemoglobin level as shown by a positive correlation between each of the cytokines and the hemoglobin level: Phlebotomy caused a significant reduction in the secretion of the four measured cytokines. Transfusion of autologous blood led to a significant rise in cytokine secretion above prephlebotomy levels which persisted throughout the study. These results suggest that the anemia of uremia may be associated with a decreased secretion of cytokines in vitro. This could contribute to the impaired immune response observed in patients with ESRD. Furthermore, RBC appear to potentiate secretion of cytokines. The decreased secretion of cytokines may be corrected in part by RBC transfusion or elevation of hemoglobin levels with rHuEpo treatment.