Background: Children with acute myeloid leukemia (AML) have a 70% survival rate with treatment regimens containing high doses of cytarabine and anthracyclines and, in some, hematopoietic stem cell transplantation (allo-HSCT). Procedure: In this multicenter Dutch–Belgian protocol (DB AML-01), 112 children with de novo AML were included. Treatment was stratified according to day 15 bone marrow response after the first induction course. Poor responders received a second course without delay while good responders awaited hematological recovery. Patients achieving CR after two induction courses continued with three consolidation courses without HSCT in CR1. Results: The overall remission rate was 93.5%. After a median follow-up of 4.1 years, three-year event-free survival (EFS) was 52.6% (95% CI, 42.9%–61.3%), three-year cumulative incidence of relapse 39.7% (95% CI, 30.1%–49.0%), and three-year overall survival (OS) 74.0% (95% CI, 64.8%–81.2%). Significantly more events occurred in patients with high WBC at diagnosis or FLT3-ITD/NPM1-WT, whereas core binding factor (CBF) leukemia had a significantly better EFS. KMT2A rearrangements and age > 10 years negatively impacted OS. Conclusions: DB AML-01 response-guided therapy results in a favorable OS, particularly for children with CBF leukemia, children younger than 10 years or with initial WBC counts below 100 × 109/L. Outcome of patients with FLT3-ITD/NPM1-WT remains poor and warrants alternative treatment strategies.