Characterizing the effect of oxygen (O(2)) modulation on the brain may provide a better understanding of several clinically relevant problems, including acute mountain sickness and hyperoxic therapy in patients with traumatic brain injury or ischemia. Quantifying the O(2) effects on brain metabolism is also critical when using this physiologic maneuver to calibrate functional magnetic resonance imaging (fMRI) signals. Although intuitively crucial, the question of whether the brain's metabolic rate depends on the amount of O(2) available has not been addressed in detail previously. This can be largely attributed to the scarcity and complexity of measurement techniques. Recently, we have developed an MR method that provides a noninvasive (devoid of exogenous agents), rapid (<5 minutes), and reliable (coefficient of variant, CoV <3%) measurement of the global cerebral metabolic rate of O(2) (CMRO(2)). In the present study, we evaluated metabolic and vascular responses to manipulation of the fraction of inspired O(2) (FiO(2)). Hypoxia with 14% FiO(2) was found to increase both CMRO(2) (5.0±2.0%, N=16, P=0.02) and cerebral blood flow (CBF) (9.8±2.3%, P<0.001). However, hyperoxia decreased CMRO(2) by 10.3±1.5% (P<0.001) and 16.9±2.7% (P<0.001) for FiO(2) of 50% and 98%, respectively. The CBF showed minimal changes with hyperoxia. Our results suggest that modulation of inspired O(2) alters brain metabolism in a dose-dependent manner.