Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease for which oligonucleotide therapeutics, such as short interfering RNA (siRNA), are currently being investigated. We synthesized siRNA cross-reactive to mouse (wild-type) Htt and human (mutant) HTT and found that divalent siRNA sustained lowering of wild-type Htt, but not mutant HTT mRNA expression. However we observed near-complete silencing of both mutant HTT protein and wild-type HTT protein. Subsequent fluorescent in situ hybridization analysis shows that divalent siRNA acts predominantly on cytoplasmic mutant HTT transcripts, leaving clustered mutant HTT transcripts in the nucleus largely intact in treated HD mouse brains.