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The differential diagnoses of ring-enhancing lesions of the brain parenchyma is broad, but complete ring-enhancing lesions often indicate a neoplastic or infectious process. We present a case of a 70-year-old female with a history of multiple sclerosis (MS) who was not on current disease-modifying therapy (DMT) and was found to have a ring-enhancing lesion that mimicked a high-grade glioma. The patient underwent gross total resection, and histopathologic and molecular analysis revealed a diagnosis of progressive multifocal leukoencephalopathy (PML). A subsequent medical workup on the patient was unrevealing aside from mild lymphopenia. This is a unique case that highlights both an unusual clinical presentation and radiographic appearance of PML. There is a known associated increased risk of PML with the use of some DMTs for MS. However, this case raises the question of the possibility of developing PML years after interferon beta-1a therapy in a patient without overt immunosuppression., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Gonzalez et al.)