To assess the risks and benefits of erythropoietin versus erythrocyte transfusion in the treatment of the anemia of prematurity, we randomly assigned 19 anemic preterm infants (birth weight 988 +/- 227 gm; gestational age 27.6 +/- 1.2 weeks; age 41 +/- 15 days; all values mean +/- SD) to receive either transfusion or subcutaneously administered erythropoietin (200 units/kg every other day for 10 doses). In the 10 erythropoietin recipients, corrected reticulocyte counts increased from 2% +/- 1% to 7% +/- 2% (p less than 0.001) and hematocrits increased from 27% +/- 2% to 30% +/- 4% (p less than 0.05). In the nine infants who underwent transfusion, reticulocyte counts did not increase, but hematocrits increased from 28% +/- 4% to 41% +/- 2% after initial transfusion (p less than 0.001) and had decreased to 34% +/- 5% by day 20. Signs attributed to anemia (tachycardia, apnea with bradycardia, and poor weight gain) declined in both the erythropoietin recipients and those who underwent transfusion. However, five of nine infants who underwent transfusion had symptoms within 10 to 14 days and were given further transfusions. Marrow aspiration performed after 7 to 10 days of treatment showed that infants receiving erythropoietin had greater percentages of erythropoietic precursors (p less than 0.01), greater concentrations of mature erythroid progenitors (p less than 0.001), and higher cycling rates of erythroid progenitors (p less than 0.001). The percentage of mature stored neutrophils in marrow was lower in the erythropoietin group than in the transfusion group, resulting in an inverse myeloid/erythroid ratio (0.5:1 vs 6.2:1; p less than 0.001). After 20 days, absolute blood neutrophil counts were lower in the erythropoietin recipients (1.8 +/- 0.9 x 10(3) cells/microliters) than in the infants who underwent transfusion (3.9 +/- 1.9 x 10(3) cells/microliters; p less than 0.05). Administration of erythropoietin thus stimulated erythropoiesis and relieved signs attributed to anemia; the significance of the relative neutropenia remains to be determined. We conclude that erythropoietin administration offers promise as an alternative to erythrocyte transfusion in neonates with symptomatic anemia of prematurity.