Progressive multifocal leukoencephalopathy (PML) is a neurological disease that affects immunodeficient patients. We describe here a case of 64-year-old man with IgD type multiple myeloma (MM) who developed progressive neurological symptoms. T(2)-weighted magnetic resonance imaging of the brain showed a hyperintense non-enhancing lesion in the left frontal lobe, and analysis of the cerebrospinal fluid by polymerase chain reaction revealed the presence of John Cunningham virus (JCV) DNA. Histopathological analysis of the autopsy brain specimen with in situ hybridization assay revealed the presence of JCV DNA in the nuclei of oligodendroglia. PML in a patient with MM is rare. However, this case report suggests that PML should be suspected and relevant diagnostic examinations should be performed when MM patients present with neurological symptoms.