Working memory deficits are common in Multi Sclerosis (MS) and have been identified behaviourally in numerous studies. Despite recent advance in functional magnetic resonance imaging (fMRI), few published studies have examined cerebral activations associated with working memory dysfunction in MS. The present study examines brain activation patterns during performance of a working memory task in individual with clinically definite MS, compared to healthy controls (HC). fMRI was performed using a 1.5 Tesla GE scanner during a modified Paced Auditory Serial Addition Test (mPA-SAT). Participants were 6 individuals with MS with working memory impairment as evidenced on neuropsychological testing, 5 individuals with MS without working memory impairment, and 5 HC. Groups were demographically equivalent. Data were analyzed using Statistical Parametric Mapping (SPM99) software, with a stringent significance level (alpha < .005, voxel extent > or =8). Both MS groups and the HC group were able to perform the task, with comparable performance in terms of numbers of correct responses. Activation patterns within the HC and MS not-impaired groups were noted in similar brain regions, consistent with published observations in healthy samples That is, activations were lateralized to the left hemisphere, involving predominantly frontal regions. In contrast, the MS impaired group showed greater right frontal and right parietal lobe activation, when compared with the HC group. Thus, it appears that working memory dysfunction in MS is associated with altered patterns of cerebral activation that are related to the presence of cognitive impairement, and not solely a function of MS.