Regional cerebraovascular reactivity (CVR) to endogenous carbon dioxide (CO2) during spontaneous breathing (i.e. end-tidal partial pressure of CO2 (PETCO2) measured at rest), was substantially different from that obtained under externally applied CO2 challenge. Individual maps of CVR to endogenous CO2 showed significant inter-subject variability while CVR maps under hypercapnic challenge did not. Such inter-subject variability was not reduced by correction of respiratory effects. In addition, the CVR to end-tidal partial pressure of oxygen (PETO2) during spontaneous breathing shows less inter-subject variability. Our findings question the compatibility of using CVR during spontaneous breathing as a surrogate of CVR under hypercapnic challenge.