PURPOSE AALL0932 evaluated two randomized maintenance interventions to optimize disease-free survival (DFS) while reducing the burden of therapy in children with newly diagnosed NCI standard-risk (SR) B-acute lymphoblastic leukemia (B-ALL). METHODS AALL0932 enrolled 9,229 patients with B-ALL; 2,364 average-risk (AR) patients were randomly assigned (2 3 2 factorial design) at the start of maintenance therapy to vincristine/dexamethasone pulses every 4 (VCR/DEX4) or every 12 (VCR/DEX12) weeks, and a starting dose of once weekly oral methotrexate of 20 mg/m2 (MTX20) or 40 mg/m2 (MTX40). RESULTS Five-year event-free survival and overall survival (OS) from enrollment, for all eligible and evaluable SR B-ALL patients (n=9,226), were 92.0% (95% CI, 91.1% to 92.8%) and 96.8% (95% CI, 96.2% to 97.3%), respectively. The 5-year DFS and OS fromthe start ofmaintenance for randomly assigned AR patients were 94.6% (95% CI, 93.3% to 95.9%) and 98.5% (95% CI, 97.7% to 99.2%), respectively. The 5-year DFS and OS for patients randomly assigned to receive VCR/DEX4 (n=1,186) versus VCR/DEX12 (n=1,178) were 94.1% (95% CI, 92.2% to 96.0%) and 98.3%(95%CI, 97.2%to 99.4%) v 95.1%(95%CI, 93.3%to 96.9%) and 98.6% (95% CI, 97.7% to 99.6%), respectively (P=.86 and .69). The 5-year DFS and OS for AR patients randomly assigned to receive MTX20 versus MTX40 were 95.1% (95%CI, 93.3% to 96.8%) and 98.8% (95%CI, 97.9% to 99.7%) versus 94.2% (95% CI, 92.2% to 96.1%) and 98.1% (95% CI, 97.0% to 99.2%), respectively (P=.92 and .89). CONCLUSIONS The NCI-SR AR B-ALL who received VCR/DEX12 had outstanding outcomes despite receiving one third of the vincristine/dexamethasone pulses previously used as standard of care on Children's Oncology Group (COG) trials. The higher starting dose of MTX of 40 mg/m2 once weekly did not improve outcomes when compared with 20 mg/m2 once weekly. The decreased frequency of vincristine/dexamethasone pulses has been incorporated into frontline COG B-ALL trials to decrease the burden of therapy for patients and their families.