The R6/2 mouse is the most common mouse model used for Huntington's disease (HD), a fatal, inherited neurodegenerative CAG disorder characterized by marked brain atrophy. We scanned 47 R6/2 transgenic and 42 wildtype (WT) ex vivo mouse brains at 18 weeks of age using high resolution, three-dimensional magnetic resonance imaging (MRI) for automated voxel-based morphometry (VBM) analysis. We found differences between genotypes in specific brain structures. Many of these changes were bilateral and were found in regions known to be involved in the behavioral deficits present in both R6/2 mice and HD patients. In particular, changes were evident in the basal ganglia, hippocampus, cortex and hypothalamus. In the striatum, changes were heterogenous and reminiscent of striosomal distribution. Changes were also seen in the cerebellum, as might be expected in a mouse carrying a repeat length typical of juvenile onset HD. Many of these changes were not detected by manual 2D morphometry from the same MR images. These data indicate that VBM will be a valuable technique for in vivo measurement of developing pathology in HD transgenic mice, and may be particularly useful for correlating histologically undetectable changes with behavioral deficits.