Erythropoietin, hemoglobin, hematocrit, oxygen affinity (P50), and reticulocyte counts were measured weekly starting at 1 week of age in 10 very-low-birth-weight infants and on a single occasion in 15 healthy men. In the adults, "available oxygen" (derived from oxygen carrying capacity and P50) averaged 13.1 ml/dl blood and the mean erythropoietin level was 15.2 mU/ml. Erythropoietin levels in the infants were inversely related to concentration of hemoglobin, P50, and available oxygen. However, despite the much lower mean "available oxygen" of 9.3 ml/dl in the infants compared with that in adults (P less than 0.001), the mean erythropoietin value of 8.2 mU/ml in the infants was less than in adults (P less than 0.001). Furthermore, the erythropoietin response to decreased "available oxygen" was lowest in the least mature infants. VLBW infants often develop clinical evidence of hypoxia during the anemia of prematurity. The relatively low erythropoietin levels in relation to "available oxygen" are compatible with a decreased erythropoietin response to hypoxia compared with that in adults. Such a difference in response could be a contributing factor to the anemia of prematurity.