A retrospective comparison evaluating survival in two well-matched cohorts of patients with cytologically positive neoplastic meningitis (NM) presenting with or without encephalopathy. Two cohorts were studied: 20 with and 20 without of NM-related encephalopathy defined as a confusional syndrome. Cohorts were matched with respect to age, primary tumor, performance status, absence of CSF compartmentalization and absence of neuroradiographic bulky CNS disease. Primary tumor histology included the following: breast(10 patients); non-small cell lung cancer (8); non-Hodgkin's lymphoma (8); colorectal cancer (6); melanoma (4); small cell lung cancer (2); prostate cancer (2). NM at presentation revealed: encephalopathy (20 patients); spinal cord dysfunction (18); and cranial neuropathy (15). Radiotherapy was administered to 31 patients (whole brain only in 17 patients; restricted spine only in 8 patients; whole brain and restricted spine in 6 patients). All patients received intraventricular chemotherapy and 16 patients received concurrent tumor-specific systemic chemotherapy. Median survival was 2.5 months (range 1.5-5 months) in the cohort with NM-related encephalopathy compared to 6 months (range: 2-10 months) in the cohort without NM-related encephalopathy (p < 0.001). No treatment-related deaths were observed. All patients demonstrated progressive disease and died of either NM or systemic cancer. NM-related encephalopathy is a clinical variable that predicts for poor survival in patients with NM. As a consequence, patients with NM-related encephalopathy may be best served by offering supportive care.