Fatigue is one of the most disabling symptoms in multiple sclerosis (MS) and there is increasing evidence it has a central origin. Our aim was to assess the impact of mental fatigue on motor task-related cerebral activation. Ten relapsing-remitting MS patients with fatigue were recruited and compared with seven controls. Functional magnetic resonance imaging (fMRI) data were acquired while subjects performed a finger-thumb apposition task. The Paced-Auditory-Serial Addition Task (PASAT) was administered to induce fatigue and the fMRI motor paradigm was then repeated. Our results revealed that the PASAT altered the MS patients' activation patterns on the motor task. After the mentally fatiguing PASAT task, repeating the motor task was associated with patients recruiting significantly more of their brain including bilateral cingulate gyri and left primary sensory cortex, while activating less of the left premotor and supplementary motor area. The control subjects decreased their level of activation after the PASAT. Our current results reveal that a challenging mental task can alter the pattern and increase the volume of cerebral activation on an unrelated motor task in fatigued MS patients. These data support the hypothesis that a substrate for MS fatigue could be a generally elevated demand placed on functioning neural circuits.