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Progressive multifocal leukoencephalopathy is a neurological disease caused by the human polyoma virus JC virus and can present in patients with known immunodeficiencies. However, when associated with idiopathic CD4+ lymphocytopenia, management of patients can be quite challenging as these are two rare diseases with limited effective treatment options. In conjunction with the case report of a patient diagnosed with both conditions presented within this issue, a discussion of available treatment strategies is detailed.