Abstract Objectives: To shorten the scanning protocol for quantification of cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2), a new method has been developed using 15O-CO 2, CO, O 2 and PET. Methods: Fifteen patients with carotid occlusion or stenosis were employed. One-minute inhalation of 15O-CO and 3-min static scanning and blood sampling was performed to measure cerebral blood volume (CBV). With 2-min inhalation of 3 GBq 15O-CO 2, serial dynamic scanning and arterial blood sampling was performed for 6 min. With 15-min inhalation of 15O-O 2, steady state O 2 image was scanned for 5 min, and arterial blood and plasma were sampled to measure oxygen extraction fraction (OEF) and CMRO2. In addition, to compare with conventional method, steady state CO 2 image was scanned for 5 min with 15-min inhalation of 7.5 GBq 15O-CO 2 and arterial blood and plasma sampling. CBF and partition coefficient of water in the brain were estimated by non-linear curve fitting to the tissue time-activity curves. A new method was developed to measure OEF and CMRO2 using the known ratio of arterial H 2O and O 2 concentration in O 2 steady state. The method does not require measuring the plasma counts. For each subject, about 2000 regions of interest (ROIs) were positioned, estimates calculated from a new method (newCBF, newOEF, newCMRO2) were correlated with those from conventional steady state method (ssCBF, ssOEF, ssCMRO2). Results: newCBF, newOEF and newCMRO2 presented significant correlation with those from steady state method, respectively (newCBF (ml/min/100 g)=1.07 ssCBF (ml/min/100 g)+3.17, r=0.934, p<0.001; newOEF=0.77 ssOEF−0.01, r=0.707, p<0.001; newCMRO2 (ml/min/100 g)=0.95 ssCMRO2 (ml/min/100 g)+0.04, r=0.856, p<0.001). The length of the scanning period was reduced 20 min and cut to 35 min for each patient to perform the new protocol study to measure CBF, OEF and CMRO2 without arterial plasma sampling. New method was able to reduce 4.5 GBq of 15O-CO 2 inhalation compared with the steady state method. Conclusion: We have developed a new method that permits quantitative measurement of CBF, OEF and CMRO2 with a short period acquisition time without arterial plasma sampling. The method also reduces radiation exposure of patients. This protocol may be of great value in clinical brain PET using 15O gas.