The reactions of cerebral metabolism to imposed changes of cerebral blood flow (CBF) are poorly understood. A common explanation of the mismatched CBF and oxygen consumption (CMR(O(2))) during neuronal excitation holds that blood flow rises more than oxygen consumption to compensate for an absent oxygen reserve in brain mitochondria. The claim conversely implies that oxygen consumption must decline when blood flow declines. As the prevailing rate of reaction of oxygen with cytochrome c oxidase is linked to the tension of oxygen, the claim fails to explain how oxygen consumption is maintained during moderate reductions of CBF imposed by hyperventilation (hypocapnia) or cyclooxygenase (COX) inhibition. To resolve this contradiction, we extended the previously published oxygen delivery model with a term allowing for the adjustment of the affinity of cytochrome c oxidase to a prevailing oxygen tension. The extended model predicted constant oxygen consumption at moderately reduced blood flow. We determined the change of affinity of cytochrome c oxidase in the extended model by measuring CBF in seven, and CMR(O(2)) in five, young healthy volunteers before and during COX inhibition with indomethacin. The average CBF declined 35%, while neither regional nor average CMR(O(2)) changed significantly. The adjustment of cytochrome c oxidase affinity to the declining oxygen delivery could be ascribed to a hypothetical factor with several properties in common with nitric oxide.