Primary central nervous system lymphoma (PCNSL) is an unusual form of non-Hodgkin’s lymphoma that is restricted to the central nervous system. Although it presents with focal neurologic symptoms, it is characterized pathologically by diffuse infiltration of the brain. PCNSL is sensitive to corticosteroids, radiotherapy, and chemotherapy. High-dose methotrexate–based regimens form the cornerstone of multimodality therapy and have significantly improved response rates and survival. Prolonged survival can be associated with devastating neurotoxicity to which the elderly are particularly susceptible.