Increasing evidence supports a role for abnormal immune activation and inflammatory responses in Huntington disease (HD). In this study, we evaluated the therapeutic potential of laquinimod (1 and 10 mg/kg), a novel immunomodulatory agent shown to be protective in a number of neuroinflammatory conditions, in the YAC128 mouse model of HD. Treatment with laquinimod for 6 months rescued atrophy in the striatum, in certain cortical regions, and in the corpus callosum of YAC128 HD mice. Diffusion tensor imaging showed that white matter microstructural abnormalities in the posterior corpus callosum were improved following treatment with low dose (1 mg/kg) laquinimod, and were paralleled by reduced levels of interleukin-6 in the periphery of YAC128 HD mice. Functionally, treatment with laquinimod (1 and 10 mg/kg) led to modest improvements in motor function and in depressive-like behaviour. Taken together, these results suggest that laquinimod may improve some features of pathology in HD, and provides support for the role of immune activation in the pathogenesis of HD.Huntington disease (HD) is an inherited, progressive neurodegenerative disorder caused by a dominant mutation in huntingtin (HTT), a ubiquitously expressed gene 1 . The clinical phenotype of HD includes psychiatric disturbances such as depression and psychosis, cognitive deficits, and impairment of motor function with abnormal voluntary (gait, balance, hand movements) and involuntary movements (chorea and dystonia) 1 . Neuropathologically, the disease is characterised by striking atrophy of the striatum and thinning of the cortex, which is accompanied by early and progressive white matter loss 1 . Volumetric MRI changes in HD include pronounced caudate atrophy accompanied by putaminal and whole brain atrophy early in the disease course 2 . Despite the significant unmet need and intensive efforts to develop therapies over the past three decades, no effective treatment to reverse, stop or slow the progression of HD has been identified 3 .Several disease mechanisms have been implicated in HD, including aberrant synaptic signalling, transcriptional dysregulation, altered proteolysis, impaired intracellular trafficking, and loss of neurotrophic support 4 . Increasing evidence also supports a role for abnormal immune activation and inflammatory responses in HD 5-8 . Significant accumulation of microglia, the CNS-resident macrophage, is seen in regions with neuronal