We have developed, implemented, and validated a method for the measurement of the local cerebral metabolic rate for oxygen (CMRO2) with positron emission tomography (PET). We use data from a single inhalation of O-15-labeled CO for cerebral blood volume (CBV), an intravenous injection of [O-15]H2O for cerebral blood flow (CBF), and a single inhalation of [O-15]O2 for the final calculation of CMRO2 and the extraction of oxygen (E). The mathematical model used to analyze the data consists of two compartments and accounts for production and egress of water metabolism in the tissue, recirculating water of metabolism, and the arterial, venous, and capillary contents of [O-15]O2 in the brain. We validated our technique in baboons by comparing the PET-measured E with E measured using an intracarotid injection of [O-15]O2. The correlation between these two techniques was excellent. Mathematical simulations were done to examine the effect of errors in CBV, CBF, and recirculating water of metabolism on the measurement of E and CMRO2. The technique was implemented on five normal human subjects in whom the global CMRO2 was 2.93 +/- 0.37 (s.d.) ml/min X 100 g.