A prospective study of combined modality therapy of non-AIDS related lymphomatous meningitis was carried out. Lymphomatous meningitis is diagnosed increasingly as anti-lymphoma therapies become more effective and result in prolonged patient survival. Twenty-two patients (range 38-69 years; median 60) with lymphomatous meningitis due to metastatic non-AIDS related non-Hodgkins lymphoma were treated. Neurologic presentation included: headache (n=13); cranial neuropathies (n=9); ataxia (n=5); cauda equina syndrome (n=3); myelopathy (n=1); and meningismus (n=1). All patients underwent radiographic evaluation of the extent of central nervous system disease (CNS) followed by radiotherapy (n=8) and sequential intraventricular chemotherapy (methotrexate in 22 patients; cytarabine in 12; thio-TEPA in 5). CNS imaging demonstrated: interrupted CSF now (n=8); intra-cranial subarachnoid nodules (n=2); hydrocephalus (n=2); spinal subarachnoid nodules (2); nerve root enhancement (n=2); and epidural spinal cord compression (n=1). Cytologic responses were seen in 16 patients (73%) to first-, 7 (58%) to second- and 2 (40%) to third-line chemotherapy. Treatment-related toxicity included 14 patients (64%) with aseptic meningitis and 12 patients (55%) with thrombocytopenia or neutropenia (all unrelated to intraventricular chemotherapy). Median survival was 10 months (range: 3-24 months). Fourteen patients (64%) died of their systemic disease, 3 patients (14%) died of progressive lymphomatous meningitis, 4 patients (19%) died of progressive combined systemic disease in lymphomatous meningitis and 1 patient (5%) is disease-free. Fourteen patients (64%) received concurrent systemic chemotherapy and no differences were seen in outcome within this group of patients including 6 patients treated with dose intensive chemotherapy and autologous bone marrow transplantation. Lymphomatous meningitis in patients with non-AIDS related non-Hodgkin's lymphoma may be palliated with combined modality therapy, however, despite the application of standard or dose intensive systemic chemotherapy, therapy remains non-curative.