Primary central nervous system lymphoma (PCNSL) can develop in the setting of profound immunosuppression, including late-stage infection with HIV. The management of such patients has yet to be defined optimally and differs substantially from that of immunocompetent patients who have PCNSL. The clinical features, diagnosis, and management of AIDS-related PCNSL are reviewed. The authors focus on commonly encountered diagnostic and therapeutic dilemmas and explore some promises and pitfalls of Epstein-Barr virus-directed therapies.