The YAC128 mouse model of Huntington disease (HD) exhibits motor abnormalities, cognitive dysfunction and selective neuropathology which are similar to the human disease. Backcrossing YAC128 mice from the FVB/N strain onto the C57BL/6 strain and the 129 strain revealed that striatal volume loss and motor dysfunction are penetrant on all three genetic backgrounds. The severity of HD-like phenotypes in these mice is modulated by strain and this variation is not accounted for by differences in mutant huntingtin expression. In contrast, nuclear localization of mutant htt is modulated by strain and is correlated with the severity of neuropathology. Differences in phenotypic severity between the strains provide the opportunity to identify modifier genes which could impact the pathogenesis of HD. Importantly, the demonstration of penetrance across all three strains permits examining the effect of specific genes on the phenotypic severity in YAC128 mice without necessarily backcrossing onto the FVB/N strain background.