A method for estimating regional cerebral blood flow is described in which tracer amounts of 138 Xe are inhaled for 2 min and monitored extracranially over the next 45 to 60 min. A three-compartment model used to analyze the resulting clearance curves provided separate blood flows for "gray" and "white" matter, plus a decay constant for a slow third component, believed to arise from extracerebral tissue. The analysis included a correction for recirculation of all three components, based on radioisotope concentration of the expired air or arterial blood. Results from the analysis were compared with those obtained by the more traditional two-compartment approach, using data from 15 healthy young males. Whereas the three-compartment method yielded measurements comparable with those obtained by established techniques (average CBF = 54.7 ml/100 g/min), the two-compartment analysis gave consistently lower values (average CBF = 30.2). Comparison of results based on expired air and arterial sampling suggested that end-expiratory air is a reasonable substitute for arterial blood. Although the I3S Xe inhalation method is technically simpler and less traumatic than other methods, complex analytic treatment of the data is necessitated by the presence of appreciable recirculation and extracerebral contamination. • In 1963 Lassen and co-workers (1) introduced a method for measuring regional cerebral blood flow in man that has yielded results (2, 3) consistent with older established techniques. This method involves the extracranial monitoring of an inert, diffusible radioisotope (85-krypton or 133-xenon) injected into the internal carotid artery. The clearance curves so obtained are subjected to a twocompartment analysis (4, 5) in which separate