We examined the acute effects of a change in hemoglobin oxygen affinity (P50) on systemic oxygen transport and oxygen consumption during hypoxia. Ten awake, intact, newborn lambs were studied during four consecutive conditions: normoxia (Fio2=0.21); hypoxia (Fio2=0.10); hypoxia after isovolemic exchange transfusion, raising P508 ± 3 Torr without changing hematocrit; and normoxia after the exchange transfusion. With hypoxia, oxygen extraction rose, cardiac output increased minimally, and systemic oxygen transport and oxygen consumption fell. After exchange transfusion during hypoxia, oxygen consumption rose to resting levels due to a significant augmentation of systemic oxygen transport, which resulted from an increase in cardiac output. This change in cardiac output was due to an increased stroke volume, most likely due to an improved inotropic state. The above findings are consistent with observations in newborn infants with respiratory distress syndrome who underwent exchange transfusion.