Progressive multifocal leukoencephalopathy (PML) is a usually fatal cerebral white matter disease found in patients with human immunodeficiency virus infection and other immunocompromised states. We present the case of a 63-year-old woman with polycythemia vera who developed a progressive focal neurological deficit with white matter abnormalities on magnetic resonance images of the brain that was proved on biopsy to be PML. She was treated with the serotonin reuptake inhibitor mirtazapine and remains neurologically stable, with resolution of cerebral lesions, >2 years after diagnosis. We propose that mirtazapine should be investigated further for use in PML.