We compared the 133Xe clearance method and the microsphere technique (15-μm spheres) for cerebral blood flow determination in 15 mongrel dogs. The 133Xe clearance curve obtained from sampling dorsal sagittal sinus blood following left ventricular injection showed either two or three components. Blood flow calculated from the first component can be correlated with the average gray matter blood flow through the caudate nucleus, the cortical gray, and the thalamus calculated from the microsphere data. The second component of the 133Xe curve correlated well with the white matter blood flow measured with microspheres. In seven out of 15 experiments, there was a third component in the 133Xe clearance curve. The blood flow obtained from the third component showed a close correlation with extracranial muscle blood flow determined with microspheres. The mean cerebral blood flow measured with the 133Xe clearance method was in close agreement with that obtained by the microsphere technique. After the injection of 133Xe into extracranial muscles, the slope of the clearance curve obtained from the dorsal sagittal sinus correlated well with that of the third component following left ventricular injection. The results indicate that regional cerebral blood flows measured with 15-μm microsphere can be correlated with those obtained from various components of the simultaneous 133Xe clearance. These findings also point out the necessity of considering the contribution of extracranial muscles when analyzing the 133Xe clearance curve.