In historical studies erythropoietin stimulated bone marrow was shown to produce less stable, macrocytic, "stress erythrocytes". Recent work from our lab suggests that erythropoietin serves as both a growth factor and as a survival factor. To investigate the effects of recombinant human erythropoietin (rHuEPO) on development of red blood cell size of these longer lived erythrocytes, rHuEPO in 50-150 U/kg/dose was administered to patients with the anemia of chronic renal failure (CRF). Mean corpuscular volume (MCV) was determined at control, short term (n = 117, avg. 53 d), intermediate term (n = 73, avg. 136 d) and at long term (n = 66, avg. 221d) for effects of rHuEPO. Statistical evaluation at these time points was made comparing all patients to themselves as their own controls and using contingency tables for distribution of RBC size change. MCV at both short term (p = .02) and intermediate-term (p < .01) was decreased; there was no change (p = .71) at the long term. Analysis of distribution showed a significant (p < .01) trend toward microcytosis at short- and intermediate terms. This decrease of MCV and trend toward microcytosis is consistent with iron deficiency secondary to the early, rapid increase in bone marrow iron utilization and early increased reticulocytosis. Previous reports from our laboratory coupled with data presented in this report refute earlier findings that rHuEPO creates a "stress" mechanism producing less stable macrocytes.