A 71-year-old man with CLL diagnosed two years prior developed cognitive decline over several weeks, followed by progressive left hemiparesis over the previous ten days. He had previously declined chemotherapy for CLL and pursued homeopathic treatment only. His initial brain MRI was interpreted as showing subacute-chronic infarcts throughout the right-greater-than-left subcortical white matter and right anterior, posterior and internal border zones. A follow-up MRI obtained 18 days later noted interval worsening of diffusion restriction and FLAIR hyperintensities involving right>left bilateral cerebral hemispheres. Differential diagnosis at that time included atypical progression of subacute infarcts, CNS vasculitis, intravascular lymphoma and less likely PML. Cerebrospinal fluid (CSF) studies showed pleocytosis with markedly increased small lymphoid cells, hyperproteinorrachia, and JC virus PCR of 91121 IU/mL. Brain biopsy was obtained, ultimately confirming a demyelinating lesion most consistent with PML. During his hospitalization, he suffered numerous systemic complications, including septic shock, cardiogenic shock, acute hypoxic respiratory failure, and acute kidney injury requiring renal replacement therapy. PML is especially difficult to treat with worse outcomes in patients with hematological malignancies due to the difficulty treating immune dysfunction. Off-label treatment with Pembrolizumab was considered, but the family ultimately opted for comfort measures, the patient was terminally extubated and passed shortly thereafter.