A 53-year-old man with an 18-year history of multiple sclerosis (MS) was treated with natalizumab for 7 years. Two years prior to presentation, natalizumab treatment interval was increased to every 6 weeks in attempt to reduce the risk of PML. Medical history was notable for cutaneous T-cell lymphoma status-post CHOP chemotherapy. JCV serology was positive (index 2.8). He presented to our tertiary referral center for consultation due to 8 months of progressive left-sided paresthesias, 4 months of right arm clumsiness, and several weeks of expressive aphasia. Neurologic examination was consistent with these symptoms. Serial brain MRIs demonstrated progressive development of a subcortical, multifocal T2/fluid-attenuated inversion recovery hyperintensity in the left frontoparietal white matter (figure 1). Subtle but definite MRI abnormalities were present in the same area 12 months prior. His clinical course and MRI findings prompted urgent evaluation for PML.