A 78-year-old white male with chronic pancytopenia presented with acute transient aphasia and dysarthria. He had a National Institutes of Health Stroke Scale (NIHSS) of zero. Physical examination revealed slight aphasia with mild dysarthria. Brain magnetic resonance imaging (MRI) revealed nine ring-enhancing lesions in the left precentral gyrus with significant vasogenic edema. Lung computed tomography (CT) showed no evidence of pulmonary nodules. The serology of blood and urine for infectious organisms was negative. Four weeks later, the patient was re-admitted with worsening dysarthria and right upper extremity weakness. Repeat head MRI showed a slight increase in the size of the multiple supratentorial ring-enhancing lesions. The magnetic resonance spectroscopy (MRS) findings of the evaluated lesion suggested a fungal etiology. Empiric amphotericin B treatment was initiated, which mitigated central nervous system (CNS) ringenhancing lesions and resolved the patient's neurological deficits. Early empiric medical treatment of CNS histoplasmosis should be considered in the setting of multiple CNS ring-enhancing lesions and a positive history of histoplasmosis infection, despite negative serological studies.