Quantitative assessment of brain oxygen extraction fraction (OEF) is of substantial clinical significance in many brain diseases. However, a remaining issue associated with OEF is its considerable inter-subject variations within healthy population. Therefore, it is important to investigate the physiological underpinnings of OEF variations among normal subjects. The present work used two studies, a discovery study and a verification study, to examine the extent to which end-tidal CO2 (EtCO2) can explain inter-subject variations in OEF. It was found that, across subjects, OEF is inversely correlated with EtCO2, and EtCO2 alone can account for about 50% of variances in OEF.