Legacy data show that approximately 40% of children with acute lymphoblastic leukemia (ALL) were cured with limited antimetabolite-based chemotherapy regimens. However, identifying patients with very-low-risk (VLR) ALL remains imprecise. Patients selected based on a combination of presenting features and a minimal residual disease (MRD) level of <0.01% on day 19 of induction therapy had excellent outcomes with low-intensity treatment. We investigated the impact of MRD levels between 0.001% and <0.01% early in remission induction on the outcome of VLR ALL treated with a low-intensity regimen. Between October 2011 and September 2015, 200 consecutive patients with B-precursor ALL with favorable clinicopathologic features and MRD levels of <0.01%, as assessed by flow cytometry in the bone marrow on day 19 and at the end of induction therapy, received reduced-intensity therapy. The 5-year event-free survival was 89.5% (± 2.2% SE), and the overall survival was 95.5% (± 1.5% SE). The 5-year cumulative incidence of relapse (CIR) was 7% (95% CI, 4% to 11%). MRD levels between 0.001% and <0.01% on day 19 were detectable in 29 patients. These patients had a 5-year CIR significantly higher than that of patients with undetectable residual leukemia (17.2% ± 7.2% vs 5.3% ± 1.7%, respectively; P = .02). Our study shows that children with VLR ALL can be treated successfully with decreased-intensity therapy, and it suggests that the classification criteria for VLR can be further refined by using a more sensitive MRD assay.