Primary central nervous system (CNS) lymphoma is the most common brain tumor in patients with AIDS and occurs in about 10% of this population. CT/MR scan usually demonstrates single or multiple contrast enhancing masses that are radiographically indistinguishable from other CNS processes such as toxoplasmosis. Brain biopsy, positive cerebrospinal fluid (CSF) cytology, or possibly the demonstration of Epstein-Barr viral DNA in the CSF can establish the diagnosis. Cranial radiotherapy (RT) has been the cornerstone of therapy and produces responses in most patients, but their median survival is still only a few months. The addition of chemotherapy to RT may prolong survival in a sub-group of patients.