Positron emission tomography (PET) of [18F]fluoromethane (FM) and single-photon emission tomography (SPECT) of [99mTc]hexamethylpropyleneamine oxime (HMPAO) were performed under identical conditions within 2 h in 22 patients suffering from cerebrovascular disease (8 ischemic infarction, 2 intracerebral hemorrhages, 7 transient ischemic attacks, and 5 multi-infarct syndrome). While gross pathological changes could be seen in the images of either procedure, focal abnormalities corresponding to transient ischemic deficits or to lesions in multi-infarct syndrome and areas of functional deactivation were sometimes missed on SPECT images. Overall, HMPAO SPECT images showed less contrast between high and low activity regions than the FM PET images, and differences between lesions and contralateral regions were less pronounced (6.4 vs 13.3% difference). Regional cerebral blood flow (rCBF) was calculated from FM PET studies in 14 large territorial regions and the pathological lesion, and the regional values relative to mean flow were compared to the relative HMPAO uptake in an identical set of regions defined on the SPECT images. Among individual patients, the Spearman rank-correlation coefficient between relative rCBF and HMPAO uptake varied between 0.48 and 0.89, with a mean of 0.70. While an underestimation of high flow with SPECT--which was demonstrated in a curvilinear relationship between all relative regional PET and SPECT values--could be corrected by linearization taking into account HMPAO efflux from the brain before metabolic trapping, correspondence of SPECT data with PET rCBF values was not improved since this procedure also increased the variance in high flow areas. In the cerebellum, however, a high HMPAO uptake in SPECT always overestimated CBF in relation to forebrain values; this finding might be due to high capillary density in the cerebellum. The differences observed between SPECT and PET data may be explained by technical and physical properties of the methods and by the incomplete first-pass extraction of HMPAO. Additionally, HMPAO or its metabolites may leak through a damaged blood-brain barrier (as observed in one infarct and in the surrounding of hemorrhages), impairing the contrast between lesion and normal tissue. The presented data indicate that the quantification of rCBF by HMPAO SPECT is limited.