Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by the expression of mutant huntingtin protein (Htt). Suppression of Htt expression, using RNA interference, might be an effective therapy. However, if reduction of wild-type protein is not well tolerated in the brain, it may be necessary to suppress just the product of the mutant allele. We present a small interfering RNA (siRNA) that selectively reduces the endogenous mRNA for a heterozygous HD donor's pathogenic allele by approximately 80% by specifically targeting a single-nucleotide polymorphism (SNP) located several thousand bases downstream from the disease-causing mutation. In addition, we show selective suppression of endogenous mutant Htt protein, using this siRNA. We further present a method, using just a heterozygous patient's own mRNA, to determine which SNP variants correspond to the mutant allele. The method may be useful in any disorder in which a targeted SNP is far downstream from the pathogenic mutation. These results indicate that allele-specific treatment for Huntington's disease may be clinically feasible and practical.