The neurodegenerative disorder Huntington disease (HD) appears to be caused by an increase in the number of repeats of the trinucleotide CAG located near the 5′ end of the gene. The nucleotide sequences of the cDNA and the gene predict that the HD protein has a molecular weight of 347 000 (3144 amino acids) and that the CAG repeats encode a segment of polyglutamine beginning 17 amino acids from the amino terminus. Because the CAG repeat plays such a critical role in the etiology of the disease, we sought to obtain evidence that the polyglutamine segment is indeed present in the protein. We used two peptides, hd1-peptide (FESLKSFQQ), predicted to lie at amino acid positions 11-19, just amino-terminal to the polyglutamine segment, and hd2-peptide (QQPRNKPLK), predicted to lie at amino acid positions 2531-2539, to induce polyclonal antibodies in NZW rabbits. Both antibodies recognize a protein on Western blots of about 350 kDa in cell lysates from human brain tissue and human and monkey cell lines, including cells from individuals heterozygous and homozygous for the disease. These results suggest that the HD protein in these cells contains the predicted amino terminal segment, and by inference, the segment of polyglutamine, and that the protein is expressed even when only mutant copies of the gene are present. Interestingly, the antibody to hd1-peptide does not recognize the HD protein on Western blots containing lysates from rodent cell lines, whereas the antibody to hd2-peptide does. This discrimination provides a useful means to assay for the presence of the human HD protein in a rodent cell background. / 1995 Oxford University Press.