The Children's Cancer and Leukemia Study Group (CCLSG) has conducted, since 1981, a series of protocols for treatment of acute lymphoblastic leukemia (ALL) in childhood. In a randomized control study of the 811 protocol (1981-1983) for standard-risk ALL, an intermittent cyclic regimen of an intermediate-dose of methotrexate (MTX) plus 6-mercaptopurine (6MP) showed significant superiority for maintenance chemotherapy as compared with conventional continuous administration of a low dose of the two drugs. The event-free survival (EFS) rate at 10 years was 65.4% for the intermittent cyclic regimen, while the EFS rate of continuous regimen was 36.1% (P < 0.01). The intermittent cyclic regimen may also be effective in preventing extramedullary relapses. In the 841 protocol (1984-1987), the three-drug induction therapy consisting of vincristine (VCR), prednisone (PDN) and L-asparaginase (L-ASP) improved the EFS rate (94.1% at 8 years) as compared with the two-drug therapy consisting of VCR and PDN (64.1%, P < 0.05). In the 874 protocol (1987-1990) two regimens with or without cranial irradiation for standard-risk patients were compared with respect to their ability to prevent central nervous system (CNS) leukemia and to improve overall outcome of ALL. The regimen with cranial irradiation showed a 79.9% EFS rate at 5 years, whereas the regimen without cranial irradiation demonstrated a 69.1% EFS rate (not significantly). Life-table analysis of serial CCLSG protocols for ALL in which the cyclic administration of intermediate-dose MTX plus 6MP has been standardized as maintenance therapy revealed that the outcome of allover ALL has gradually improved with increase of the EFS rate; 41.4% for the 811 protocol, 51.4% for the 841 protocol to 54.4% for the more recent 874 protocol.