<p>Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the central nervous system caused by reactivation of John Cunningham (JC) virus in a subset of immunocompromised individuals. This case report describes a rare case of progressive cavitary lesion in PML with only one other documented case in the world. The patient is a 63-year old male with medical history of microscopic polyangiitis who had previously undergone cyclophosphamide treatment and was on chronic immunosuppression with mycophenolate and high dose prednisone who presented to the emergency department with stroke-like symptoms. A series of magnetic resonance imaging (MRI) demonstrated a non-enhancing multifocal lesion in his frontal lobe that progressed into a cavitary lesion. PML was diagnosed using imaging presence of periventricular white matter lesions and positive JC virus in the cerebrospinal fluid. Stereotactic biopsy followed by histological staining of the samples and immunohistochemistry confirmed the diagnosis. We emphasize cavitary lesions as an extremely rare, but potential development of PML that appears to correlate with aggressive neurocognitive decline and has no identified associations.</p>