Preferential loss of basal ganglia neurons and terminals occurs in Huntington's disease (HD). Terminals of preproenkephalin medium-size spiny neurons are more vulnerable than terminals of preprotachykinin neurons, but the peptidergic neurons of origin have not yet been shown to die preferentially. We sought to determine, in the striatum, whether preproenkephalin neurons were lost to a greater extent than preprotachykinin neurons and to determine whether there were decreases in specific messenger RNA (mRNA) levels of preproenkephalin, preprotachykinin, and calbindin D28k. We found a grade-related decrease in the number of preprotachykinin- and calbindin D28k-labeled neurons per measuring field in the caudate nucleus of patients with HD. Three measures of the neuronal level of preprotachykinin mRNA were all significantly reduced (6-65% of control values) in HD caudate nucleus. No decline in calbindin D28k mRNA levels per neuron were found in HD striata compared to control striata. We found a greater loss of preproenkephalin neurons per field than preprotachyknin neurons per field in the caudate nucleus of HD brains compared to control brains. Preprotachykinin neurons are lost in HD in a grade-related manner and surviving preprotachykinin neurons are impaired in function. However, preproenkephalin neurons are lost to a greater extent than preprotachykinin neurons, which may explain preferential changes found in projection regions of the striatum. Declines in neuropeptide mRNA may be specific in HD, since calbindin D28k mRNA levels were unchanged. Alterations in the levels of expression of preproenkephalin and preprotachykinin mRNA may be direct or indirect effects of the HD mutation.