Subjective fatigue is a typical symptom in Multiple Sclerosis (MS) even in the earliest stages of the disease. The relationship between persistent fatigue and motor task performance is still unclear. Aim of this study was to better investigate this relationship at both the motor behavioral and neuroanatomical levels. Towards this goal, we combined a quantitative evaluation of an undemanding finger motor task with concurrent brain functional magnetic resonance imaging (fMRI) in a group of MS patients with minimal disability but reporting persistent subjective fatigue. We found an unexpected significant positive correlation between persistent subjective fatigue and task-related temporal accuracy, revealing a "fatigue-motor performance paradox". fMRI analysis indicated that this association is potentially mediated by cerebellar and orbitofrontal cortex activity, suggesting a role of these regions in developing subjective fatigue. Our data point to a possible adaptive role for fatigue as the subjective correlate of increased resource demand for motor activities.