CT and MRI are not consistently able to differentiate central nervous system (CNS) lymphoma from focal cerebral infection such as toxoplasmosis in the human immunodeficiency virus (HIV) involvement. In this study thallium 201 (and/or technetium-MIBI) SPECT was performed in 6 patients suffering from AIDS and CNS lesions. An index based on the ratio of thallium uptake in the lesion vs the contralateral scalp was calculated. In 4 out of 5 patients with lymphoma (3 confirmed by biopsy, 2 highly suspected on CT and resistance to antitoxoplasmosis treatment) focal lesions showed high uptake of thallium. On the other hand one markedly necrotic lymphoma and all infectious lesions did not take up thallium. This suggests a role for thallium 201 brain SPECT in the workup of focal CNS lesions in AIDS.