We examined the distribution of neuropeptide Y immunoreactive local circuit neurons and nonphosphorylated neurofilament (SMI 32) immunoreactive pyramidal projection neurons in superior frontal cortex of patients with Huntington's disease and age-matched control subjects to determine the histological counterpart of increased neuropeptide Y and decrease glutamate concentrations previously found in the cortex of patients with Huntington's disease. We found no difference between the relative density of neuropeptide Y neurons in Huntington's disease and control brains in regions where the relative density of SMI 32 immunoreactive was significantly reduced. Animal studies show that cortical local circuit neurons are resistant to N-methyl-D-aspartate-type excitotoxins such as quinolinic acid. Relative sparing of neuropeptide Y neurons in cerebral cortex with Huntington's disease may, therefore, be a result of excessive N-methyl-D-aspartate receptor activation.