Involvement of the central nervous system (CNS) by Histoplasma capsulatum is a rare event. It is usually not included in the differential diagnosis of CNS lesions in patients with acquired immunodeficiency syndrome (AIDS). Herein are described four patients with AIDS and progressive disseminated histoplasmosis who had CNS involvement. Histoplasmosis in the CNS may produce meningitis, single or multiple brain abscesses, and may present with either a clinical picture of obtundation or a deteriorating space-occupying CNS lesion. Three of the four patients were treated with amphotericin B and had initial clinical response, but ultimately, all experienced a relapse and died from their infection.