Administration of recombinant erythropoietin (EPO) has been shown to decrease or eliminate the need for erythrocyte transfusion (Tx) in preterm infants and to decrease the need for Tx in late anemia due to Rh or ABO hemolytic disease. The objective of this study was to determine if EPO administration to infants with hemolytic anemia before one month of age will prevent severe anemia and avoid the need for Tx. A planned randomized, controlled study could not be done due to parents' preference for EPO therapy once relative risks of EPO vs transfusion had been explained. Eighteen term infants were treated with EPO between 8/96 and 11/97. The etiology of the hemolytic anemia was as follows: 10 ABO incompatibility (7/10 with positive direct Coombs), 1 hemolytic elliptocytosis, 1 G6PD deficiency, 2 alpha thal. trait, 4 unknown (1 had Hb SS). At the start of EPO therapy, ages were 1.5-3.5 wks (med 2 wks), Hb levels 9-13.5 gm/dL (med 10.1; all but 1 had Hb < 11.4), reticulocytes 0.6-2.6% (med 1.5%). Serum EPO levels in 10 of these infants ranged from 2.5-20.3 mU/mL (med 9.6 mU/mL). All infants received EPO 200 u/kg SC TIW for a duration of 2-5.5 wks (med 3 wks) with oral iron 3 mg/kg day during EPO therapy and for an additional 6 wks. The reticulocyte counts increased 2-10 fold from pre-EPO values in 1-2 wks. Hb levels remained stable or increased during EPO therapy except in 1 infant with OB hemolytic disease who developed a UTI and was transfused for worsening anemia. In most infants the Hb level remained stable or declined slightly (< 1 gm/dL) after EPO was discontinued, but EPO administration was resumed in 1 infant when the Hb level dropped from 11.4 to 10.1 gms/dL during the first week off therapy. No adverse effects were observed from EPO administration. We conclude that serum EPO levels are not increased in term infants with hemolytic anemia. EPO administration results in brisk reticulocyte response with stable or increasing Hb levels and, thus, is likely to prevent or reduce the need for Tx.