Background Natalizumab is prescribed in Italy in patients who experienced at least two clinical relapses during a 12-month therapy with other approved immunomodulatory agents. Results In 7 of 35 patients selected on the basis of these recommendations, we have observed clinical relapses occurring within 24 h after the first dose of natalizumab. Conclusion The mechanism by which a first injection of natalizumab may precipitate a clinical relapse in patients with MS is unknown. We speculate that natalizumab can promote the release of inflammatory mediators from lymphocytes present in the central nervous system at the time of the first infusion, thus favoring the clinical manifestation of a pre-existing active lesion.