Objectives: This randomized controlled trial tested the hypothesis that children with non-high-risk acute lymphoblastic leukemia could benefit from individualized 6-mercaptopurine increments during consolidation therapy (NCT00816049). Primary and secondary end points were end of consolidation minimal residual disease (MRD) positivity and event-free survival. Methods: 392 patients were randomized to experimental and 396 to standard therapy. Patients allocated to standard therapy received oral 6-mercaptopurine (25 mg/m²/day) from days 30 to 85, while the experimental arm received stepwise increments of additional 25 mg/m²/day beginning on days 50 and/or 71 unless dose-limiting myelosuppression had occurred. Results: In the experimental arm, 166 patients (42%) received one dose increment, and 62 (16%) received two. Fifty-seven of 387 (15%) patients in the experimental arm were MRD positive at end of consolidation vs 77 of 389 (20%) in the control arm (P =.08). Five-year probability of event-free survival was 0.89 (95% CI: 0.85-0.93) in the experimental arm vs 0.93 (0.90-0.96) in the control arm (P =.13). The median accumulated length of 6-mercaptopurine treatment interruptions was 7 (IQR 2-12) in the experimental arm vs 4 (IQR 0-10) in the control arm (P =.002). Conclusion: This study found no benefit from individualized 6-mercaptopurine increments compared to standard therapy.