A 48-year-old woman with multiple sclerosis (MS), treated with natalizumab for more than one year without clinical and magnetic resonance imaging (MRI) signs of disease activity, was diagnosed with definite progressive multifocal leukoencephalopathy (PML). She presented with subacute motor deficit of the right upper limb (UL), followed by involvement of the homolateral leg and urinary urgency. The patient was treated with steroids and plasma exchange. On follow-up MRI scans, the PML lesion remained stable and no MS rebounds were observed, but the patient complained of a progressive worsening of the right UL motor impairment, becoming dependent in most activities of daily living. A cycle of multidisciplinary rehabilitation (MDR) was then started, including daily sessions of UL robot therapy and occupational therapy. Functional MRI (fMRI) was acquired before and at the end of the MDR cycle using a motor task which consisted of 2 runs: in one run the patient was asked to observe while the second one consisted of hand grasping movements. At the end of the rehabilitation period, both the velocity and the smoothness of arm trajectories during robot-based reaching movements were significantly improved. After MDR, compared with baseline, fMRI showed significantly increased functional activation within the sensory-motor network in the active, motor task, while no significant differences were found in the observational task. MDR in MS, including robot-assisted UL training, seems to be clinically efficacious and to have a significant impact on brain functional reorganization on a short-term, even in the presence of superimposed tissue damage provoked by PML.