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Introduction: Natalizumab (NTZ) is an effective drug for the treatment of relapsing-remitting multiple sclerosis. In some patients discontinuation is mandatory due to the risk of progressive multifocal leukoencephalopathy. However, severe clinical and radiological worsening has been described after drug cessation. Our aim was to describe the clinical and radiological features of the rebound phenomenon., Material and Methods: Patients switched from NTZ to Fingolimod (FTY) who had presented a rebound after discontinuation were selected. Clinical and magnetic resonance imaging (MRI) data were collected., Results: Four JC virus positive patients were included. The mean disease duration was 9.5 years ( SD : 4.12) with a mean time of 3.1 years on NTZ. All patients started FTY within 3-4 months. Neurological deterioration started in a mean time of 3.5 months ( SD : 2.08) with multifocal involvement: 75% motor disturbances, 50% cognitive impairment, 25% seizures. The average worsening in Expanded Disability Status Scale [EDSS] was of 3.25 points ( SD : 2.33). The MRI showed a very large increase in T2 and gadolinium-enhanced lesions (mean: 23.67, SD : 18.58). All patients received 5 days of IV methylprednisolone, one patient required plasma exchange. All the patients presented neurological deterioration with an EDSS worsening of 1.13 points ( SD : 0.48). After the rebound three patients continued treatment with FTY, only one patient restarted NTZ., Conclusion: Discontinuation of NTZ treatment may trigger a severe rebound with marked clinical and radiological worsening. A very careful evaluation of benefit-risk should be considered before NTZ withdrawal, and a close monitoring and a short washout period is recommended after drug withdrawal.