It has recently been reported in a-chloralose anesthetized rats that the hemodynamic response to somatosensory stimulation almost doubled following transient hypercapnia (THC). In principle, this effect could be employed to enhance the sensitivity of perfusion-based fMRI experiments. To investigate whether a comparable effect was detectable in awake normal humans, changes in cerebral blood flow (Delta CBF) and the effective transverse relaxation time (DeltaT(2)*) induced by a visual search task were measured in 10 healthy volunteers before and after THC. Concerning DeltaT(2)*: no significant differences were found, whereas in four subjects Delta CBF was significantly decreased (p < 0.01) following THC. These results demonstrate no increase in the CBF response following THC for awake humans. We conclude that the most likely explanation for this discrepancy with the earlier results obtained with animals is an as yet unknown mechanism of modulation of the cholinergic system by the anesthesia. Copyright (C) 2000 John Wiley & Sons, Ltd.