Structural imaging studies such as CT or MRI are not able to accurately differentiate infectious from malignant cerebral lesions in patients with AIDS. We studied 11 individuals with AIDS and central nervous system (CNS) lesions with 18F-fluoro-2-deoxyglucose (FDG) and positron emission tomography (PET). FDG-PET was able to accurately differentiate between a malignant (lymphoma) and nonmalignant etiology for the CNS lesions. Both qualitative visual inspection of the images as well as semiquantitative analysis using count ratios was performed and revealed similar results. FDG-PET may be useful in the management of AIDS patients with CNS lesions since high FDG uptake most likely represents a malignant process which should be biopsied for confirmation rather than treated presumptively as infectious.