Thirty-eight adults with acute lymphocytic leukemia (ALL), 24 previously untreated and 14 previously treated, were entered into a study in which sequential, moderate-dose methotrexate and asparaginase were added to vincristine and dexamethasone (MOAD) for remission induction therapy. Eighteen of 24 previously untreated patients (75%) and 11 of 4 previously treated patients (79%) achieved a complete remission (CR). Once in CR, patients were given remission continuation therapy, which included intravenous high-dose methotrexate that was used without prophylactic cranial irradiation and without intrathecal methotrexate because of its potential activity alone as prophylaxis against central nervous system (CNS) leukemia. The median duration of CR was 11.1 mo (range 0.7–55.9+) and median survival 17.0 mo (range 0.4- 55.9+) for the 24 previously untreated patients. The median duration of CR was 7.5 mo (range 1.9–55.3+) for the 14 previously treated patients. Only 2 of 24 previously untreated patients (8.3%) developed CNS leukemia at 3.3 and 42.7 mo from start of MOAD. None of the previously treated patients developed CNS leukemia as the initial site of relapse. MOAD is useful as induction therapy for previously untreated adults with ALL, as well as for previously treated patients, and is superior to other regimens that we have used for the treatment of adult ALL.