In the present study we assess the effect of recombinant human erythropoietin (r-HuEpo) upon levels of fetal Hb (HbF) and adult Hb (HbA) in preterm infants. Twenty-eight "healthy," appropriate for gestational age infants with birth weights 900-1400 g entered the study at 3 wk of age. Fourteen infants were randomized to receive r-HuEpo, and 14 infants served as controls. Four controls and six r-HuEpo treated infants had been transfused before study start, whereas four control infants were transfused in the course of the study. The untransfused infants showed a high HbF/Hb ratio during the study with only a weak tendency to decline toward the expected time of delivery. The total Hb mass increased (p < 0.05) more in the r-HuEpo-treated infants than in the untreated, whereas the rise in HbF mass was similar in the two groups. After each transfusion, the HbF/Hb ratio reverted gradually to the ratio expected at the infant's postconceptional age. There was no difference in the production rate of HbF between r-HuEpo-treated infants and controls. The present data indicate that the HbF/HbA ratio in preterm infants is subject to the same programmed mechanisms which govern intrauterine erythropoiesis until term and that exogenous r-HuEpo does not influence this pattern significantly.