Primary central nervous system lymphoma (PCL) is an uncommon form of non-Hodgkin’s lymphoma located outside the lymph nodes. It usually involves the brain, meninges, eye or spinal cord and there is no evidence of systemic involvement. Untreated PCL progresses rapidly and death usually occurs within 1.5 months of diagnosis. Patient survival after whole brain radiotherapy usually increases to 12-18 months. If radiotherapy is followed by chemotherapy or chemotherapy followed by radiotherapy, the mean survival can be increased to 36-48 months. However, whole brain radiotherapy, especially in elderly patients, has a high potential for complicating symptomatic neurotoxicity. There is no most appropriate treatment option for PCL. When possible, patients should be advised to participate in clinical trials. The main treatment option for PCL is methotrexate-based induction chemotherapy. A uniform treatment regimen is inconclusive. Treatment includes chemotherapy, whole brain radiotherapy and high dose followed by autologous hematopoietic cell transplantation. The aim of PCL treatment is to prolong survival. 1. For patients who decide to give chemotherapy, we recommend high-dose methotrexate-based induction chemotherapy rather than whole-brain radiotherapy alone. Those patients in good general condition who do not choose to participate in clinical trials, we recommend giving methotrexate in combination with cytarabine rather than one methotrexate alone. Options for chemotherapy include: methotrexate, temozolomide, rituximab (MTR) or rituximab, methotrexate, and methylbutyrazine (R-MPV). 2. For patients who cannot tolerate high-dose methotrexate induction therapy, chemotherapy regimens (including: temozolomide and rituximab rituximab; cytarabine and etoposide; or anti-folate agents other than methotrexate) or palliative regimens are available. Palliative regimens include whole brain radiotherapy or steroid hormones alone. Holistic Unification The most appropriate holistic treatment regimen is inconclusive. The options are: chemotherapy, autologous hematopoietic cell transplantation or whole-brain radiotherapy. 1. For younger patients, who achieve complete remission after high-dose chemotherapy, we recommend deferring radiotherapy rather than giving it immediately after chemotherapy 2. Patients older than 60 years are at higher risk of symptomatic neurotoxicity after radiotherapy. For such patients, we recommend deferring radiotherapy until disease progression occurs, rather than giving whole brain radiotherapy immediately after chemotherapy. In young patients with recalcitrant lymphoma, a second chemotherapy regimen (cytarabine, etoposide) should be given after methotrexate-based chemotherapy has failed to achieve complete remission, and autologous hematopoietic cell transplantation may be used as an acceptable treatment option in patients who are partially effective on initial therapy. In such patients, we also consider the administration of whole-brain radiotherapy right after the completion of chemotherapy, rather than waiting for the disease to progress again. Follow-up: After the initial planned treatment regimen is completed, the disease is not considered cured. Patients should be evaluated to see how they respond to treatment and to observe for relapses, as well as to see if there is any toxicity from the long course of treatment. Relapse: Treatment after relapse includes re-treatment with high doses of methotrexate for patients in complete remission after initial methotrexate treatment. Additional chemotherapy regimens include cytarabine and etoposide, autologous hematopoietic cell transplantation (HDT/HCT), and whole brain radiation therapy.