The aim of this study was to trace the possible relation between degree of cognitive impairment in Huntington's disease (HD) and cortical cerebral blood flow. We studied 18 patients with genetically confirmed HD, evaluating clinical signs and performance on neuropsychological tests. SPECT with 99mTc-HMPAO was used to quantify regional cerebral blood flow (rCBF) in 8 regions in each hemisphere. We found no correlation between clinical or cognitive variables and rCBF in temporal, parietal or occipital areas. Cognitive performance on several tasks correlated significantly with rCBF (p < 0.05 or p < 0.01) in numerous frontal areas with the exception of orbital gyri. These data suggest that frontal lobe dysfunction is implicated in the pathogenesis of cognitive impairment in HD, and that such impairment can be explained by the involvement of frontal-subcortical loops.