Background: Macro-and micro-structural neuroimaging measures provide valuable information on the patho-physiology of Huntington's disease (HD) and are proposed as biomarkers. Despite theoretical advantages of mi-crostructural measures in terms of sensitivity to pathology, there is little evidence directly comparing the two. Methods: 40 controls and 61 early HD subjects underwent 3 T MRI (T1-and diffusion-weighted), as part of the PADDINGTON study. Macrostructural volumetrics were obtained for the whole brain, caudate, putamen, corpus callosum (CC) and ventricles. Microstructural diffusion metrics of fractional anisotropy (FA), mean-, radial-and axial-diffusivity (MD, RD, AD) were computed for white matter (WM), CC, caudate and putamen. Group differences were examined adjusting for age, gender and site. A formal comparison of effect sizes determined which modality and metrics provided a statistically significant advantage over others. Results: Macrostructural measures showed decreased regional and global volume in HD (pb 0.001); except the ventricles which were enlarged (pb 0.01). In HD, FA was increased in the deep grey-matter structures (pb 0.001), and decreased in the WM (CC, p=0.035; WM, p =0.053); diffusivity metrics (MD, RD, AD) were increased for all brain regions (pb 0.001). The largest effect sizes were for putamen volume, caudate volume and putamen diffusivity (AD, RD and MD); each was significantly larger than those for all other metrics (pb 0.05). Conclusion: The highest performing macro-and micro-structural metrics had similar sensitivity to HD pathology quantified via effect sizes. Region-of-interest may be more important than imaging modality, with deep grey-matter regions outperforming the CC and global measures, for both volume and diffusivity. FA appears to be relatively insensitive to disease effects.