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To evaluate clinicopathological features associated with leptomeningeal disease in systemic AIDS-related non-Hodgkin's lymphoma (NHL) and to compare outcomes to those without leptomeningeal disease. In addition to evaluate intrathecal chemoprophylaxis for patients with good immunological parameters and high risk of meningeal relapse (bone marrow, paraspinal or paranasal involvement or Burkitt's lymphoma histology).Prospective data, which has been collected on our cohort of 8640 HIV seropositive patients treated at the Chelsea and Westminster Hospital includes 176 patients with systemic AIDS-related NHL, was analysed.At presentation, 18 (10%) patients had meningeal involvement. There were significant associations between meningeal disease and both Burkitt's lymphoma and paraspinal or paranasal involvement. There was no difference in the overall survival between patients with or without meningeal involvement at presentation (Kaplan–Meier log-rank, P = 0.35) and the 1-year actuarial survivals are 25% [95% confidence interval (CI), 3–47%] for patients with meningeal involvement and 33% (95% CI, 26–41%) for those without. Prophylactic intrathecal chemotherapy was administered to 21 high-risk patients and four (19%) relapsed with meningeal disease.This single-centre experience of a large cohort has demonstrated that meningeal involvement at presentation correlates with Burkitt's lymphoma histology and paraspinal or paranasal space disease, but not with bone marrow lymphoma. It also documents that long-term survival is achievable rarely in patients who present with meningeal disease and in patients with isolated meningeal relapse.