The effect of carbon dioxide (CO(2)) 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 (DeltaCMRO(2)), and relies on the assumption of a stable CMRO(2) during CO(2) 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 DeltaCMRO(2) measurements made noninvasively in humans during graded hypercapnia and hypocapnia. We used computerized end-tidal CO(2) modulation to minimize undesired concurrent changes in oxygen pressure, and our findings suggest that no significant change in global CMRO(2) is expected at the levels of end-tidal CO(2) changes customary to calibrated BOLD.