Objectives: The objective of this study was to evaluate clinical and microbiological characteristics of Chagas disease (ChD) with central nervous system (CNS) involvement in AIDS patients. Methods: This was a retrospective study of clinical and laboratory findings of HIV-infected patients with a confirmed diagnosis of ChD involving the CNS during the period 1992-2007 at the ''Francisco J. Mun ˜iz'' Infectious Diseases Hospital, Buenos Aires, Argentina. Results: Of a total of 15 patients, 14 were male and the median age was 33 years (range 25-54 years). Seven out of nine had lived in a Chagas endemic area and 7/10 were intravenous drug users (IDUs). The disease was reactivated during corticosteroid therapy in three patients. Clinical manifestations were: headache (11/15), focal neurological deficits (9/15), fever (9/15), meningismus (7/15), seizures (7/15), altered mental status (5/15), and cardiac involvement (3/10). The median CD4 T-cell count at the time of reactivation was 64 cells/ml (range 1-240). Twelve of 14 had positive serology for Trypanosoma cruzi; the two negative were IDUs. Cerebrospinal fluid (CSF) findings (median (range)): cell count 5/mm 3 (2-90), protein level 0.68 g/l (0.1-1.84), and glucose level 0.45 g/l (0.13-0.73). CSF direct examination for T. cruzi was positive in 11/13. Neuroimaging findings showed a single hypodense lesion in 7/14 and normal images in 2/14. Twelve patients were treated with benznidazole. The global mortality was 79% (11/14). Conclusions: ChD reactivation should be considered as a differential diagnosis of meningoencephalitis in HIV patients with low CD4 T-cell counts, previous residency in an endemic area, and/or IDUs. Whenever possible, lumbar puncture should be performed because of the high accuracy for early diagnosis.