Mirtazapine has recently emerged as a promising agent for the treatment of progressive multifocal leukoencephalopathy (PML). While there is no Class I evidence for its use, numerous case reports have illustrated mirtazapine's efficacy. True to its name, PML is known to occur mostly in the white matter of the brain as its causative agent, John Cunningham virus (JC virus), has a predilection for infecting glial cells. The virus replicates vigorously in oligodendrocytes and causes lysis of the glial cell culminating in demyelination. Therefore, gray matter involvement is rare. Mirtazapine's 5HT2A receptor blocking capacity is presumed to hinder JC virus' entry into glial cells. We report a case of a patient with human immunodeficiency virus (HIV) with predominantly gray matter lesions from JC virus reactivation. This case is the first reported case of gray matter PML in an Arabic patient who responded favorably to mirtazapine therapy.