Central nervous system (CNS) aspergillosis is a relatively uncommon complication of human immunodeficiency virus (HIV) infection. We describe 6 patients with the acquired immunodeficiency syndrome (AIDS) who developed CNS aspergillosis, and we review a total of 33 cases of CNS aspergillosis among HIV-infected individuals that were diagnosed by histology and/or culture. All patients were diagnosed with advanced HIV infection. Major risk factors for the disease included neutropenia and corticosteroid use. The most common presenting symptoms were nonspecific neurologic manifestations including headache, cranial or somatic nerve weakness or paresthesia, altered mental status, and seizures. The most common sites of additional Aspergillus involvement were the lungs, sinuses, ears, and orbits, while in one-fourth of the cases CNS was the only site of Aspergillus infection. The final diagnosis of CNS aspergillosis was made on autopsy in more than half the cases, and medical treatment of CNS aspergillosis was unsuccessful in all cases. CNS aspergillosis should be included in the differential diagnosis of HIV-infected patients who present with nonspecific neurologic symptoms and signs. If we take into account the much higher prevalence of invasive aspergillosis of the lungs, the findings in the present report suggest that CNS aspergillosis in HIV-infected individuals occurs more often as a result of direct extension from the sinuses, orbits, and ears than through hematogenous spread from the lungs. Physicians should be aware that the CNS might be the only site of Aspergillus involvement and include CNS aspergillosis in the differential diagnosis of HIV-infected patients presenting with focal neurologic signs and symptoms, especially when the head CT reveals hypodense lesions.