Knowing the good penetration of systemic HDara-C into the CNS, we treated with this approach overt meningeal leukemia, either isolated or with bone marrow (BM) disease, in 31 adults: 18 ALL, 4 ANLL, 1 lymphoid blast crisis of CGL (LBC-CGL), and 8 non-Hodgkin's lymphoma (NHL). Treatment consisted of Ara-C, 3 g/m2 i.v. q 12 h, by 3 h infusion for 8 doses, followed by 4 doses at day 21. Complete remitters received consolidation with four monthly 4-dose courses of HDara-C. Additional multidrug consolidation and direct CNS therapy with intrathecal (i.t.) methotrexate (MTX) or Ara-C +/- cranial RT was administered to the 11 remitters last treated. Twenty of 31 patients (64%) achieved CR: 10/10 with isolated meningeal leukemia and 10/21 with concurrent CNS and BM disease. Of the remaining 11 patients, 8 had cerebrospinal fluid (CSF) clearing with persistent BM disease. In all cases but one CNS symptoms resolved promptly. CR median duration was 6 months (range 2 to 20). The main toxicity was myelosuppression requiring intensive support. There was no neurologic toxicity. These results show that systemic HDara-C is highly effective in acute leukemias and NHL with CNS involvement, and suggest the utility of this regimen for sanctuary chemoprophylaxis in patients at high risk for CNS disease.