Premature infants have been shown to have inadequate Epo response to anemia and early Epo administration may attenuate anemia in these infants; little is known about Epo response to non-physiologic anemia in term infants and experience with Epo therapy is limited. The objectives of this study were to determine (a) the Epo levels in anemic term infants and (b) the effect of Epo administration on retic and Hb levels. We obtained serum Epo levels in 10 infants (ages 1-5 wks) with anemia of varying or uncertain causes. Hb levels ranged from 7.9-10.4 gms/dl (median 9.5) with retic 0.6-3%. Serum Epo levels were low in 3, normal in 5 and moderately increased in 2 infants (2.5-23.9 mu/ml, median 8.3) despite significant anemia. Eleven anemic term infants(including 4 from the above group with inappropriately low serum Epo levels) received recombinant Epo (200u/kg SC tiw) and oral iron supplementation. The duration of Epo therapy ranged from 2.5 to 6 wks and iron was continued for an additional 2 months. At the start of Epo, the age of the infants ranged from 3-38 days (median 21 days), Hb ranged from 7.9-13.6 gm/dl (median 9.5) and retic was between 0.6 and 3.2%. A brisk retic response (2.8-7.7%, median 5%) was seen within a week of Epo administration in 8/11 infants followed by an increase in Hb level by the end of the second week. Of the remaining infants, one had a modest retic response with slow increase in Hb level, and another with OB isoimmune hemolytic anemia had a decline in Hb level despite retic response and received RBC transfusion 10 days after starting Epo. In conclusion, preliminary evidence suggests that (a) term infants with non-physiologic anemia may have inappropriately low levels of Epo and (b) Epo administration results in reticulocytosis, and increased Hb levels in most patients, and may obviate the need for blood transfusion. Some infants, particularly those with active hemolytic anemia, may become progressively anemic despite retic response. A randomized trial to clarify the role of Epo therapy in anemic term infants is underway.