Purpose: In an effort to improve outcome for children with advanced B- cell malignancies, a treatment plan based an a published regimen that consists of four courses of fractionated cyclophosphamide (cyclo) given with doxorubicin (doxo) and vincristine (VCR) was intensified by alternating with sequential high-dose methotrexate (MTX) and cytarabine (Ara-C), given in conjunction with intrathecal (IT) MTX and Ara-C. Patients and Methods: From October 1986 to October 1992, 133 eligible patients were enrolled: 74 with B- cell (surface immunoglobulin-positive [SIg+]) acute lymphoblastic leukemia (B-ALL) and 59 with stage IV small noncleaved-cell lymphoma (SNCCL). The median age was 8 years; there were 103 males and 30 females. Abdominal tumor masses were prominent in 63 cases (33 B-ALL and 30 stage IV SNCCL). CNS disease was present at diagnosis in 36 patients (19 B-ALL and 17 stage IV SNCCL). Results: Complete remission (CR) was achieved in 66 B-ALL and 57 stage IV patients (93% overall). At 4 years, the estimated event-free survival (EFS) rate is 65% ± 8% for patients with B-ALL and 79% ± 9% for those with stage IV SNCCL. Among patients with CNS involvement, 23 of 36 remain in CR (4-year EFS rate, 64% ± 13%). Relapses occurred early; only three patients relapsed after completion of therapy. Thirteen relapses occurred in the morrow, three in the CNS, and six in other sites. Of 11 CNS- positive patients who relapsed, only two recurred primarily in the CNS. Conclusion: The results of this study indicate that with intensified chemotherapy an increasing potential for cure exists for patients with B-ALL and stage IV SNCCL.