Although the incidence of primary central nervous system lymphoma has recently declined among people with acquired immunodeficiency syndrome, the incidence of primary central nervous system lymphoma remains high among the immunocompetent population >/=60 years of age. Elderly patients represent an important subgroup that accounts for approximately half of primary central nervous system lymphoma cases. Radiotherapy (RT) alone has produced disappointing results in the elderly. Improved clinical outcomes have been achieved with high-dose methotrexate-based chemotherapy regimens in combination with whole-brain RT. Unfortunately, combination therapy exposes elderly patients to a high risk of severe delayed neurotoxicity in up to 80%. Chemotherapy alone may be the best approach for treating elderly patients and appears to be more effective than RT, while considerably reducing the risk of neurotoxicity. Clinical studies are needed to define the optimal chemotherapy regimen for the elderly in an effort to delay or completely avoid the need for RT.