Extract: In view of previous studies which did not show a precise relation between the percentage fetal hemoglobin and the position of the oxygen hemoglobin equilibrium curve, this problem was reexamined taking into account both the concentration of fetal hemoglobin and the 2,3-diphosphoglycerate (2,3-DPG) content of the cell. Forty-eight normal infants weighing 2500 g or more at birth were studied on days 1 and 5 of life and then at 3 and 6–9 weeks, and at 3–4, 5–6, and 8–11 months of age. Fifty-six ingfants ranging in birth weight from 900 to 2420 g were studied during the first 8 days of life and then at 2− to 3-week intervals until approximately 16 weeks of life. Twelve premature infants who were ill with the respiratory distress syndrome were also studied. Laboratory procedures consisted of measurement of total hemoglobin, fetal hemoglobin, red cell 2,3-DPG, and oxygen equilibrium curves. The “functioning DPG fraction” in millimicromoles per milliliter red blood cells (RBC) was obtained by multiplication of the total red cell DPG content (millimicromoles per milliliter RBC) by the percentage of adult hemoglobin. These studies confirm previous observations that the term infant begins life with blood that has an increased affinity for oxygen. During the first few months of life the oxygen-hemoglobin equilibrium curve gradually shifts to the right and between 4 and 6 months of age becomes similar to that observed in the normal adult. The change in P60 in these infants correlated neither with the change in red cell DPG content alone nor with the decline in fetal hemoglobin alone. Instead, the progressive decrease in oxygen affinity during the first 6 months of life correlated significantly (r = 0.876, P < 0.001) with the functioning DPG fraction. The term “functioning DPG fraction” is suggested to reflect the fact that both the DPG concentration and the adult hemoglobin concentration within the cell, with which the DPG interacts, are necessary factors in determining the position of the oxygen equilibrium curve. Infants with respiratory distress appear to have P50 s that are lower than those of healthy infants of similar gestational age and birth weight. This appears to be primarily a result of a decrease in red cell DPG concentration. It is this type of infant who may benefit from exchange transfusion with fresh adult blood.