Progressive Multifocal Leukoencephalopathy (PML) is a serious condition secondary to John Cunningham virus (JCV) infection derived from an innate or acquired cellular immunity deficiency. We present the first reported case in Latin America of PML associated with Natalizumab (NZB) in a patient with a diagnostic of relapsing - remitting multiple sclerosis, who entered the emergency room with progressive cognitive, behavioral, motor and language impairment. Neuroimaging performed with magnetic resonance imaging was suggestive of PML. Polymerase chain reactions in cerebrospinal fluid for JC virus were conducted twice with negative results. Finally the diagnosis was confirmed by in situ hybridization technique on brain biopsy. This report is made in order to highlight the importance of clinical and paraclinical monitoring in patients with multiple sclerosis receiving NZB.