We describe the clinical course of a patient with multiple sclerosis in whom progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the central nervous system, developed during treatment wit interferon beta-1a and a selective adhesion-molecule blocker, natalizumab. The first PML lesion apparent on magnetic resonance imaging was indistinguishable from a multiple sclerosis lesion. Despite treatment wit corticosteroids, cidofovir, and intravenous immune globulin, PML progressed rapidly, rendering the patient quadriparetic, globally aphasic, and minimally responsive. Three months after natalizumab therapy as discontinued, changes consistent with an immune-reconstitution inflammatory syndrome developed. The patient was treated with systemic cytarabine, and two months later, his condition has improved.