The effect of carbon dioxide (CO₂) on cerebral metabolism is of tremendous interest to functional imaging. In particular, mild-to-moderate hypercapnia is routinely used in calibrated blood oxygen-level dependent (BOLD)-functional magnetic resonance imaging (fMRI)-based quantification of cerebral oxidative metabolism changes (ΔCMRO₂), and relies on the assumption of a stable CMRO₂ during CO₂ challenges. However, this assumption has been challenged by certain animal studies, necessitating its verification in humans and under conditions customary to fMRI. We report, for the first time, on global ΔCMRO₂ measurements made noninvasively in humans during graded hypercapnia and hypocapnia. We used computerized end-tidal CO₂ modulation to minimize undesired concurrent changes in oxygen pressure, and our findings suggest that no significant change in global CMRO₂ is expected at the levels of end-tidal CO₂ changes customary to calibrated BOLD.