Extraversion and Neuroticism are two fundamental dimensions of human personality that influence cognitive functioning in healthy subjects. Little is known about personality changes that may occur in patients with multiple sclerosis (MS) nor about, in particular, their neurofunctional basis. The aim of this study is to determine the impact of personality characteristics on brain activity in patients with MS. Eighteen patients with clinically definite relapsing-remitting MS without any evidence of psychiatric or cognitive disorders and thirteen healthy controls matched for age, gender and education were investigated using functional magnetic resonance imaging (fMRI) during the execution of an "n-back" task. No differences were detected on the behavioral tests between the two groups, although the MS patients had lower total IQ and showed a trend towards higher Extraversion and Neuroticism scores than did the controls. fMRI analyses demonstrated that Extraversion scores were positively associated with brain activity in the fronto-parietal network including the superior parietal lobule and dorsolateral prefrontal cortex in both groups during the high load condition of the n-back task. Given the overlapping neural systems found in the two groups, we suggest that the neural activity associated with specific personality dimension is a neurophysiological characteristic preserved in patients with MS at an early stage in the course of their disease.