Background and Objectives: The clinical importance of iron-restricted erythropoiesis in erythropoietin (EPO)-stimulated patients is controversial, Materials and Methods: We therefore reviewed 70 patients randomized into clinical trials of aggressive autologous donation and oral iron supplementation, with or without recombinant human EPO therapy. Results: Nineteen (27%) iron-depleted patients produced 5.4 +/- 2.8 ml RBC/kg compared to 4.8 +/- 2.3 ml RBC/kg (nonsignificant) in iron-replete patients due to endogenous EPO (placebo group) stimulation. EPO-treated iron-depleted patients produced 20% less RBC than iron-replete patients (8.23 +/- 3.3 vs. 10.2 +/- 4.0, p = 0.066), RBC volume expansion correlated with initial storage iron only in iron-replete patients who received EPO therapy, Conclusion: Initial storage iron status is a marginally important limitation to EPO-mediated erythropoiesis in the setting of oral iron supplementation. Strategies to maintain plasma transferrin saturation with intravenous iron therapy may be desirable to improve the erythropoietic response to EPO in this setting.