BACKGROUND: Impairments in energy metabolism are implicated in Huntington's disease (HD) pathogenesis. Reduced levels of the mitochondrial enzyme succinate dehydrogenase (SDH), the main element of complex II, are observed post mortem in the brains of HD patients, and energy metabolism defects have been identified in both presymptomatic and symptomatic HD patients. OBJECTIVE: Chemical preconditioning with 3-nitropropionic acid (3-NP), an irreversible inhibitor of SDH, has been shown to increase tolerance against experimental hypoxia in both heart and brain. Here we studied the effect of chronic preconditioning in the R6/2 mouse model of HD using mice carrying CAG repeat lengths of either 250 or 400 repeats. Both are transgenic fragment models, with 250CAG mice having a more rapid disease progression than 400CAG mice. METHODS: Low doses of 3-NP (24 mg/kg) were administered via the drinking water and the effect on phenotype progression and cognition function assessed. RESULTS: After 3-NP treatment there were significant improvements in all aspects of the behavioural phenotype, apart from body weight, with timing and magnitude of improvements dependent on both CAG repeat length and sex. Specifically, a delay in the deterioration of general health (as shown by delayed onset of glycosuria and increased survival) was seen in both male and female 400CAG mice and in female 250CAG mice and was consistent with improved appearance of 3-NP treated R6/2 mice. Male 250CAG mice showed improvements but these were short term, and 3-NP treatment eventually had deleterious effects on their survival rate. When cognitive performance of 250CAG mice was assessed using a two-choice discrimination touchscreen task, we found that female mice showed significant improvements. DISCUSSION: Together, our results support the idea that energy metabolism contributes to the pathogenesis of HD, and suggest that improving energy deficits might be a therapeutically useful target.