Increasing P50 (PO2 at 50% oxyhemoglobin saturation) reduces cerebral blood flow (CBF) during arterial normoxia. We tested the hypothesis that increasing P50 also diminishes the CBF response to isocapnic hypoxic hypoxia and that it reduces the response in proportion to the reduced normoxic CBF. P50 was increased in nine unanesthetized newborn lambs from 26.3 +/- 1.7 (+/-SE) to 36.6 +/- 2.0 Torr by isovolemic exchange transfusion with low-affinity, adult sheep blood. Microsphere-determined CBF was decreased 22% during arterial normoxia. The slope of the response curve to reduced arterial O2 content (CaO2) was proportionately attenuated by 26% with no change in O2 uptake. Consequently, O2 transport (CBF X CaO2) was reduced by a constant amount at each CaO2 level. The percentage decrease in CBF at the higher P50 was thus independent of CaO2, and the percentage increase in CBF as CaO2 fell was independent of P50: the effects of P50 and CaO2 were independent. Common to alterations in both P50 and CaO2 are alterations in capillary and tissue PO2. In this study the variable closest to capillary PO2 was sagittal sinus PO2. We found that when venous PO2 was altered by changing CaO2, the change in CBF was equivalent to that following the same alteration in venous PO2 after a change in P50. The percentage increase in venous PO2 after exchange transfusion was approximately one-half that of the increase in P50. About one-half of the potential increase in cerebral venous PO2 was therefore eliminated by a compensatory reduction in cerebral O2 transport over a wide range of CaO2.