Progressive supranuclear palsy (PSP) is a neurodegenerative disorder in which structurally preserved cerebral cortex is thought to be functionally disconnected by subcortical lesions. To assess brain functional activity in patients with PSP, we measured regional cerebral perfusion, as estimated by [123I] iofetamine (IMP) and single-photon emission computed tomography (SPECT), in 11 patients with a clinical diagnosis of PSP and 10 healthy control subjects. IMP uptake was measured in 2 basal ganglia and 24 cortical regions. Neuropsychological tests were administered to assess cognitive function. Compared to age-matched normal control subjects, relative IMP uptake was significantly reduced in PSP patients in basal ganglia (21%), superior frontal (25%), anterior parietal (19%), and inferior frontal (18%) regions. Cognitive performance was most abnormal on tests thought to be subserved predominantly by frontal lobes. Our study demonstrates that IMP-SPECT detects physiological abnormalities in the cortex that parallel behavioral impairments in PSP.