We, herein, report a 23-year-old male with a rare inherited immunodeficiency disease, hyperimmunoglobulin IgE syndrome (HIES), who developed progressive multifocal leukoencephalopathy (PML) and lymphoma simultaneously. Primary immunodeficiency of the patient has remained undiagnosed until adulthood. PML is a severe demyelinating disease of the central nervous system caused by John Cunningham virus. HIES is a rare, inherited immunodeficiency characterized by high serum levels of IgE, recurrent staphylococcal infection, eczema, and hypereosinophilia. PML may accompany primary immunodeficiency syndromes, but the association with HIES is exceedingly rare. We discuss the imaging findings, medical management, and a review of related literature on primary immunodeficiency cases complicating with PML.