OBJECTIVES: To compare the pharmacokinetics and effectiveness of continuously administered recombinant erythropoietin (Epo) in total parenteral nutrition (TPN) solution with daily subcutaneously administered Epo. METHODS: Forty preterm infants in the first 72 hours of life were randomly assigned to receive Epo (200 units/kg per day for 10 consecutive days), either subcutaneously (20 infants, 1051 ± 40 gm, 28.3 ± 0.4 weeks of gestation; mean ± SEM), or added daily to their TPN fluids (20 infants, 1028 ± 36 gm, 27.9 ± 0.4 weeks of gestation). Both groups received iron supplementation (1 mg/kg per day iron dextran in the TPN solution). Absolute reticulocyte counts and complete blood cell counts with differentials were measured, and transfusions and phlebotomy losses were recorded. Pharmacokinetics were determined in the first 16 infants. RESULTS: In the infants who received Epo subcutaneously, the elimination half-life was 17.6 ± 4.4 hours on day 3 and 11.2 ± 1.5 hours on day 10; the volume of distribution was 802 ± 190 ml/kg on day 3 and 1330 ± 243 m/kg on day 10. Serum Epo concentrations were higher on day 3 than on day 10 for both groups (subcutaneous: 400 ± 64 mU/ml vs 177 ± 29 mU/m, p <0.05; TPN: 395 ± 64 vs 194 ± 41 mU/ml, p <0.05). Clearance did not differ between the two groups with regard to route of administration and increased significantly from days 3 to 10 in both groups. Reticulocyte counts were similar in both groups. There were no differences between groups in the number of transfusions given, and the overall decline in hematocrit was similar. No adverse effects of Epo were noted in either group. CONCLUSIONS: Adding Epo to the TPN solution in this population results in similar Epo concentrations, clearance, and effectiveness as subcutaneous dosing. (J PEDIATR 1996;128:518-23)