Introduction: Progressive multifocal leukoencephalopathy (PML) is a rare, severe demyelinating disease of the central nervous system predominantly found in patients with acquired human immunodeficiency syndrome (AIDS). Case Presentation: This report details a case involving a male HIV-positive patient with PML who discontinued his highly active antiretroviral therapy (HAART) treatment 10 days after being diagnosed with HIV. The patient had no history of neurological symptoms either before or after his HIV diagnosis until he was administered corticosteroids. Notably, he began experiencing ataxia shortly after starting dexamethasone. Progressive multifocal leukoencephalopathy was diagnosed through polymerase chain reaction (PCR) testing for the John Cunningham virus (JCV) in the cerebrospinal fluid (CSF). The PML lesions were confined to the cerebellum. Conclusions: The occurrence of neurological symptoms (activation of JCV) after administering corticosteroids to a patient with HIV-who had not received any antiretroviral treatment for 4 years-raises a critical question: Is the use of corticosteroids, which are a primary treatment for immune reconstitution inflammatory syndrome (IRIS), a double-edged sword in CNS-IRIS?