Background <p>Prednisone response (PR) remains a key early treatment indicator in pediatric acute lymphoblastic leukemia (ALL). However, its independent prognostic significance has waned with the advent of minimal residual disease (MRD)-guided risk assessment. Evaluating the enduring biological and clinical significance of PR, especially in high-risk subtypes, could enhance the precision of therapeutic approaches.</p> Methods <p>This retrospective study analyzed clinical data from 2,979 pediatric patients primarily diagnosed with acute lymphoblastic leukemia (ALL) and enrolled in the South China Children’s Leukemia Group (SCCLG-ALL)-2016 Collaborative Group between October 2016 and June 2023. Patients were categorized into “good prednisone response” (GPR) and “poor prednisone response” (PPR) groups based on their response to prednisone. Clinical characteristics were compared between groups using the chi-square test. Logistic regression was employed to analyze the correlation between prednisone response and early minimal residual disease (MRD). Survival analysis was performed using Kaplan–Meier curves, and prognostic factors were evaluated using Cox regression models.</p> Results <p>Among the 2,979 patients, 2,649 were categorized as GPR and 330 as PPR. Children in the PPR group exhibited multiple high-risk clinical features and had a poorer prognosis than those in the GPR group. However, multivariate Cox regression analysis revealed that days 15 and 33 MRD had a stronger predictive value than prednisone response. Notably, PR showed strong predictive value for MRD positivity on both Day 15 and Day 33.</p> Conclusions <p>In this large real-world Chinese cohort, PR was not an independent prognostic marker but was strongly associated with early MRD burden. These findings support the contextual use of PR as a practical surrogate for MRD in resource-limited settings, and highlight the need to reconsider its role in modern risk-adapted treatment strategies.</p>