ABSTRACT Naitalizumab is a potent monoclonal antibody approved for the treatment of relapsing-remitting multiple sclerosis (MS); however, little is known about the course of disease after cessation of therapy. The few existing reports describe different courses of disease after treatment discontinuation. Here we report on four MS patients who experienced clear clinical and radiological reactivation of the disease several months after cessation of therapy with natalizumab (15-29 months). In all cases, there was almost no clinical or radiological disease activity during natalizumab therapy. Three patients experienced a severe clinical relapse between 3 and 9 months after therapy cessation. The fourth patient developed cerebral magnetic resonance imaging (MRI) activity showing multiple new gadolinium-enhanced lesions. Due to these observations, it is recommended to weigh up the risk of disease reactivation against the risk of progressive multifocal leukoencephalopathy.