The serum transferrin receptor (TfR) level reflects iron status and the rate of erythropoiesis. This study was undertaken to assess the role of serum TfR in the iron status and erythropoiesis in very-low-birth-weight infants under conditions in which erythropoiesis is stimulated by large doses of recombinant human erythropoietin (rHuEPO) and oral iron. The first 34 infants were followed from the 3rd to 11th wk of life or until discharged. They received iron at a rate of 3 mg/kg/d. The subsequent 21 infants were given rHuEPO (300 U/kg three times a week s.c.) and iron at a rate of 6 mg/kg/d from the 3rd or 4th wk of life for a mean of 3.4 wk. With this treatment, the need for transfusion was reduced from 1.4 +/- 0.4 to 0.1 +/- 0.1 transfusions per infant (p = 0.02). The serum TfR concentrations in the rHuEPO-treated infants increased gradually to values several-fold higher than those in the untreated infants. This increase was not related to intrauterine or postnatal growth, protein intake, or serum albumin concentration. Neither was an association observed between Hb and TfR concentration. In the treated infants, the serum ferritin concentration was lower at the 4th, 5th, and 7th wk of life than in the untreated infants. The very-low-birth-weight infants who were given large doses of rHuEPO and iron had a marked rise in serum TfR concentration and a small decline in serum ferritin concentration. These events have been related to iron deficiency.