Multiple sclerosis is associated with reduced white matter integrity and deficits in key cognitive processes important for arithmetic. This study examined the relationship between white matter microstructure and academic ability in 31 youths with multiple sclerosis (aged 11–19 years) and 34 demographically matched controls. Using diffusion tensor imaging, fractional anisotropy was calculated in corpus callosum and in lateralized hemispheric lobes. Difficulties with written arithmetic ability were observed in 26% of patients. Arithmetic ability correlated with fractional anisotropy values across all segments of the corpus callosum and in right frontal and parietal regions, controlling for age (r values >0.5, P<0.005). Findings highlight the functional impact of compromised white matter microstructure across diffuse regions of the brain on mathematical ability.