AbstractWe have previously demonstrated that the transcription of neuronal repressor element‐1/neuron‐restrictive silencer element (RE1/NRSE)‐regulated genes is reduced in the brain of subjects with Huntington's disease (HD) as a result of increased binding of the repressor element‐1 silencing transcription factor/neuron‐restrictive silencer factor (REST/NRSF) to its RE1/NRSE targets. As specific non‐neuronal REST/NRSF‐regulated genes have been identified in the human genome, we exploited the possibility that the binding of REST/NRSF to its target RE1/NRSE sites may also be altered in the peripheral tissues of HD patients.Our results show that REST/NRSF occupancy is increased in lymphocytes from HD subjects, thus indicating for the first time that the activity of the RE1/NRSE sites is dysfunctional in vivo. Chromatin immunoprecipitation (ChIP) of the RE1/NRSE sites in lymphocytes may therefore be a reproducible, sensitive and specific means of searching for candidate markers of HD onset and progression.