The efficacy and safety on the addition of vincristine (VCR) and dexamethasone (DEX) pulses to maintenance therapy among childhood acute lymphoblastic leukemia (ALL) remain uncertain. Herein, we perform an open-label, multicentre, randomized, phase III clinical trial, which was conducted at nine major medical centers in Guangdong province, China. Patients were randomly assigned either the conventional maintenance therapy (control group, n=384) or the VCR/DEX pulse (treatment group, n=375). When limited to the SR cohort, 10-year EFS was 82.6% (95%CI: 75.9-89.9) in the control group and 80.7% (95%CI:74-88.1) in the treatment group (Pnon-inferiority =0.0002). Similarly, patients with IR also demonstrated that non-inferiority of the treatment group to the control group in terms of 10-year EFS (73.6%[95%CI: 67.6-80] vs 77.6%[95%CI: 71.8-83.9]); Pnon-inferiority =0.005). Among the HR cohort, compared with the control group, patients in the treatment group experienced significant benefit in terms of 10-year EFS (61.1%[95%CI:47.7-78.2] vs 72.6%[95%CI:55.6-94.7, P=0.026) and a trend towards higher 10-year OS (73.8%[95%CI:61.6-88.4] vs 87.9% [95%CI:579.2-97.5, P=0.068). In the HR cohort, the total rate of drug-induced liver injury and Grade 3 chemotherapy-induced anemia were both lower for patients in the treatment group than in the control group (55.6% vs 100%, P=0.033; 37.5% vs 60%, P=0.036). Conversely, the total prevalence of chemotherapy induced thrombocytopenia were higher for patients in the treatment group than in the control group (88.9% vs 40%, P=0.027). Pediatric acute lymphoblastic leukemia with high-risk are suitable to VCR/DEX pulse during maintenance phase for the excellent outcome, while the standard-to-intermediate-risk patients could eliminate the pulses. This article is protected by copyright. All rights reserved.