Fifteen patients with acute lymphocytic leukemia (ALL) in second or subsequent remission received intensive therapy with cyclophosphamide and single dose, rapid rate (26 cGy/min) total body irradiation (TBI) followed by bone marrow transplantation (BMT) from a histocompatible sibling match. Outcome was compared to that of 23 conventionally treated control patients in second ALL remission who presented to the same institution during the same time period but had no available transplant donor. The 15 BMT patients and 23 control patients had similar characteristics, with the exception that the BMT patients were significantly older at the time of ALL diagnosis (12.6 yr versus 5.7 yr, p = 0.01). BMT patients had a significantly increased chance of remaining disease-free for 36 mo from time on study (43% actuarial versus 5%, p = 0.004) and a greater overall survival rate at 48 mo (47% actuarial versus 9%, p = 0.27) than the conventionally treated patients. In all, 5 of the bone marrow transplant patients (33%) remain alive and free of disease 24-48 + mo from transplantation. Several pre- and posttransplant characteristics were analyzed to determine predictive factors for a successful BMT outcome for patients with ALL in second or subsequent remission. Significant risk factors for predicting leukemic relapse included initial white blood count (WBC) greater than 50,000/microliters at ALL diagnosis (100% relapse rate versus 37% for patients with lower WBCs, p = 0.001) and presence of any extramedullary disease pre-BMT (100% relapse rate versus 37% for patients without extramedullary disease, p = 0.03). All 5 disease-free BMT survivors had initial WBCs less than 50,000/microliters and no evidence of extramedullary disease pretransplantation. Maintenance chemotherapy with 6-mercaptopurine (6MP) and methotrexate was given to four patients starting 100 days after bone marrow transplantation. Use of maintenance chemotherapy was associated with a significantly increased chance of remaining disease free (100% of patients surviving leukemia-free versus 17% for patients not receiving maintenance chemotherapy, p = 0.02). Presence of graft-versus-host disease (GVHD) did not influence leukemia-free survival. These results confirm that intensive therapy followed by bone marrow transplantation is the treatment of choice for patients with ALL in second or subsequent remission who have a histocompatible sibling match. Furthermore, the data suggest that a controlled trial to evaluate the efficacy of maintenance chemotherapy post-BMT for ALL patients is warranted.