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CNS infiltration of neoplastic B-cell lymphocytes both in acute leukemia as well as in lymphoma, carry very bad prognosis. There are no universal guidelines for the prophylaxis of such CNS relapse in these patients. Current prophylactic regimes have early and late side effects, sometimes with severe toxicities. Although rituximab has improved treatment results in lymphoproliferative diseases, it cannot reach the CNS when administered systemically (Feugier, Ann Oncol 2004, Rubenstein, Blood 2004). Schulz (Haematologica 2004) used this drug in the treatment of relapse of primary brain lymphomas with positive results using a dose of 10 to 40mg, and estimated 25mg to be a good standardized dose. After approval from our ethics committee and obtaining the informed consent signature, patients received 25 mg of intrathecal rituximab (IT-R) according to the standard intrathecal regimen, plus the standard systemic chemotherapy protocol in our department. Side effects were evaluated according to the NIC toxicity scale. Nine patients have been enrolled in the protocol so far: 8 were male and 1 female, median of age was 49 years (range 14–72). A total of 57 IT-R were administered to our patients (median: 6, range 3–15). They had the following diagnosis: Two with large diffuse B cell lymphoma (LDBCL); two with mantle cell lymphoma (one of them blastic type), three with acute lymphoblastic leukemia; one with Burkitt’s lymphoma (BL) and one with anaplastic lymphoma. Two patents had initial CNS infiltration; the blastic type Mantle Cell Lymphoma (patient 2) and the anaplastic Lymphoma (patient 9); these patients received IT-R three times per week, plus two extra doses after complete remission in CNS. Median follow-up was 9 months (range: 3–15 months). All patients had risk factors that warranted prophylaxis (see table). Toxicity included headache in 35% of administrations (Grade I/II), temporal paresthesias in 24.5% of administrations (lasting a median of 5 minutes, range 2–15), neuropathic pain and vomit in 12.3% of administrations (grade I/II), fever and chills in 7% of administrations (Grade I/II). All side effects were temporary and no patient has shown neurological or other late toxicities. The patient with mantle cell lymphoma infiltrated to CNS achieved complete remission after 5 doses of IT-R which continues after autologous stem cell transplantation. The use of rituximab as IT-R is safe and effective. We are starting a phase II study using IT rituximab as prophylaxis and treatment, in a larger group of patients.