BACKGROUND The effect of normobaric hyperoxia on brain oxygenation in the presence or absence of intact autoregulation has not been studied previously in acute traumatic brain injury (TBI). METHODS In this prospective clinical investigation of 50 patients operated on for severe TBI, cerebral blood flow (CBF) velocity in the middle cerebral artery was measured using transcranial Doppler. Regional cerebral oxygen saturation using near-infrared spectroscopy at 3 different fractions of inspired oxygen (Fio2) (0.4, 0.6, and 1) was measured in the last 25 of these patients. RESULTS There was no difference in the hemodynamic and respiratory variables except for Pao2, which increased with increasing Fio2. The CBF velocities and pulsatility indices did not vary at different levels of Fio2 (0.4, 0.6, and 1) both on the operated and on the nonoperated side. The regional cerebral oxygen saturation as evaluated by bifrontal near-infrared spectroscopy sensors increased with increasing Fio2 on the operated (pathologic) side with impaired cerebral autoregulation and not with intact autoregulation. CONCLUSIONS In severe TBI, middle cerebral artery CBF velocity is not affected by hyperoxia in both the pathologic and the normal side. The cerebral oxygen saturation increased with increasing arterial hyperoxia in the operated cerebral hemisphere and remained within baseline range in the nonoperated hemisphere. Impairment in the cerebral autoregulation in the pathologic hemisphere contributes to this luxury oxygenation.