The near-IR cytochrome c oxidase (CCO) signal has potential as a clinical marker of changes in mitochondrial oxygen utilization. We examine the CCO signal response to reduced oxygen delivery in the healthy human brain. We induced a reduction in arterial oxygen saturation from baseline levels to 80% in eight healthy adult humans, while minimizing changes in end tidal carbon dioxide tension. We measured changes in the cerebral concentrations of oxidized CCO (Δ[oxCCO]), oxyhemoglobin (Δ[HbO2]), and deoxyhemoglobin (Δ[HHb]) using broadband near-IR spectroscopy (NIRS), and estimated changes in cerebral oxygen delivery (ecDO2) using pulse oximetry and transcranial Doppler ultrasonography. Results are presented as median (interquartile range). At the nadir of hypoxemia ecDO2 decreased by 9.2 (5.4 to 12.1)% (p<0.0001), Δ[oxCCO] decreased by 0.24 (0.06 to 0.28) micromoles/l (p<0.01), total hemoglobin concentration increased by 2.83 (2.27 to 4.46) micromoles/l (p<0.0001), and change in hemoglobin difference concentration (Δ[Hbdiff]=Δ[HbO2]−Δ[HHb]) decreased by 12.72 (11.32 to 16.34) micromoles/l (p<0.0001). Change in ecDO2 correlated with Δ[oxCCO] (r=0.78, p<0.001), but not with either change in total hemoglobin concentration or Δ[Hbdiff]. This is the first description of cerebral Δ[oxCCO] during hypoxemia in healthy adults. Studies are ongoing to investigate the clinical relevance of this signal in patients with traumatic brain injury.