Huntington's disease (HD) is an autosomal neurodegenerative disorder, characterized by severe motor, behavioral and cognitive decline. In this study, we examined the energy expenditure of transgenic R6/2 (120 ±10 CAGs) and WT (wild-type) mice. Both female and male R6/2 and WT mice at age of 5–6 and 11–12 weeks were used. Resting oxygen consumption (VO₂) and carbon dioxide production (VCO₂) were measured by indirect calorimetry at thermoneutral zone (+32°C) and during cold stress (slow cooling from 32 to ca. +3°C). In addition, RQ (respiratory quotient, CO₂ produced/O₂ consumed) and metabolic scope (VO₂max / BMR) values were calculated. Female transgenic R6/2 mice have an increased mass-specific energy expenditure at thermoneutrality compared to WT already at 5–6 weeks of age, and that the difference is dramatically increased at 11–12 weeks, whereas in male R6/2 mice increased energy expenditure was only observed at 11–12 weeks of age. Interestingly, the RQ values were lower in both age groups of transgenic mice, but only in females. There were no differences in metabolic scope at 5–6 weeks of age between R6/2 and WT mice. In summary, these results show that R6/2 mice have increased metabolic rate at thermoneutrality but a smaller maximum metabolic rate during cold stress. Thus R6/2 mice are not able to increase their metabolism as efficiently as WT mice when challenged with a physically demanding situation like cold. Finally, it seems that female R6/2 mice exhibit more pronounced metabolic profile than males. As non-acclimated mice react to cold by shivering thermogenesis, the results suggest impairment either in the neuromuscular control or metabolic support of muscular shivering. This assay of thermogenic capacity in transgenic mouse models of human diseases with energetic deficiency, such as in HD, is a useful screening tool for compounds on phenotypic progression, and particularly on energy metabolism.