The differentiation between progressive supranuclear palsy (PSP) and Parkinson's disease (PD) may be difficult, especially in the early stages of disease. Positron emission tomography potentially provides a tool for making such a distinction. To identify key features in the spatial distributions of cerebral glucose metabolism, 18F-fluorodeoxyglucose (FDG) measurements of 10 patients with probable or possible PSP were directly compared with those of 9 PD patients. This analysis was done with statistic parametric mapping. After normalization of global brain uptake, in PSP, relative uptake of FDG was reduced in the caudal (motor) part of the anterior cingulate gyrus (Brodmann's area BA 24; P < 0.05, corrected for multiple comparisons). At a lower threshold, an additional decrease was present in the dorsal mesencephalon. In PD, relative hypometabolism was seen in extrastriate visual, ventrolateral temporal, posterior parietal, and orbitofrontal regions. Only reduction in the right fusiform gyrus and the lateral extrastriate visual cortex reached statistical significance. We concluded that particularly the reduction of medial frontal metabolism may be a valuable diagnostic imaging parameter in distinguishing PSP from PD. For PD, a possible association between occipitotemporal FDG decrease and vulnerability to hallucinations is suggested.