Background: Indications for the use of Granulocyte colony-stimulating factors (G-CSF) have so far been suggested to prevent febrile neutropenia, as well provide support for intensive chemotherapy. However, the long-term consequences of its use in children with acute lymphoblastic leukemia (ALL), especially in the time-sequenced setting, are not yet well understood. Materials and Methods: Children with newly diagnosed acute lymphoblastic leukemia ALL in Ali Asghar Children’s Hospital were randomly assigned to two groups. Patients in both groups underwent chemotherapy according to the ALL IC-BFM 2002 protocol. Patients in Group A were supported in a time-sequenced setting during the second phase of induction and protocol mM and reinduction phase with G-CSF. However, patients in group B received G-CSF only during severe neutropenia or febrile neutropenia, as 5 μg/kg daily until there was an absolute neutrophil count (ANC) greater than 500/μl. Results: A total of 63 patients were included in the study. The total number of patients in both groups were as follows: 32 patients in group A (18 boys and 14 girls) and 31 patients in group B (11 boys and 20 girls). The number of high-risk patients in group A was higher, but this difference was not statistically significant. The recurrence rate in patients in group B was about seven times the recurrence rate in patients in group A, and the difference was statistically significant. In group A, no early relapse occurred, while nearly half of relapses in group B occurred as early relapses and the rest as late relapses. The 5-yr EFS rate was 96.90% ± 6.20% (95% CI) for patients in group A and 80.60 ± 14.20% (95% CI) for patients in group B, and this difference was statistically significant. Conclusion: In this study, prophylactic G-CSF prescribed in a time-sequenced setting not only does not increase the incidence of secondary leukemia in children with ALL but in addition to improving their prognosis, it reduces the recurrence rate in this group of patients. This finding needs to be confirmed by a larger study.