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Objective Central nervous system involvement in AIDS patients can present at any stage of the disease. Brain lesions detected in imaging studies are usually treated empirically. A brain biopsy is indicated in the absence of clinical and radiologic improvement. In the present study, 16 AIDS patients underwent brain biopsy. We evaluated the diagnostic yield of the brain biopsy and the changes in the disease course. Materials and methods Sixteen consecutive AIDS patients (12 men, 4 women; mean age 40.8 years) underwent a brain biopsy at Sheba Medical Center between 1997 and 2009. A retrospective analysis was performed and the clinical outcome was recorded. Results Median CD4 count before biopsy was 62.6. Magnetic resonance images revealed multiple lesions in 12 patients and enhancing lesions in 12 patients. A total of 19 biopsies were performed in 16 patients. In the present series, the initial procedures provided a diagnostic yield of 81.25% (13 diagnostic cases from 16 procedures in 16 patients). Two of these patients underwent repeated biopsies that were eventually diagnostic . If repeated biopsies were taken into consideration, the diagnostic yield was 93.75% (15 diagnostic cases in 16 patients). The rate of hemorrhagic complications was 10.5% (2 hemorrhages in 19 procedures). Pathologic examination revealed parasitic and fungal infections in 6 patients (6/16; 38%), progressive multifocal leukoencephalopathy in 4 patients (4/16; 25%), AIDS encephalopathy in 4 patients (4/16; 25%), and lymphoma in 1 patient (1/16; 6%). One patient had a nonspecific inflammatory process (6%). The treatment modality was modified in 12 patients and led to clinical and radiologic improvement in 8 patients. Conclusions Brain biopsy should be considered when empiric treatment of central nervous system lesions in AIDS patients fails. Biopsy is diagnostic in the majority of patients. The diagnosis allows for treatment modifications, which lead to clinical and radiologic improvement in some patients. [ABSTRACT FROM AUTHOR]