Abstract Background: Primary pediatric brain tumors are the most prevalent type of childhood tumors and the most common cause of cancer death among children. However, there is insufficient literature regarding the use of novel chemotherapy agents to treat such tumors. Therefore, the purpose of this study is to evaluate the effectiveness of Irinotecan-based chemotherapy regimen for the treatment of primary brain tumors as well as minimizing morbidity and mortality rates. Procedure: In this cross-sectional study, 88 children aged 0 to 18 years old with primary brain tumors were investigated. Data was extracted from patients’ medical records. 38 patients received Irinotecan treatment from the beginning (B) or after relapse (AB). At study termination, the response rate to the treatment as well as the Overall Survival (OS) and 6 months Progression Free Survival (6-mo-PFS) were estimated using Kaplan-Meier survival analysis and PFS estimation. Results: According to the findings of this study, pediatric brain tumors in males are more common than in females (60% in comparison to 40%). The highest incidence of brain tumors was reported in the age range of 6 to 12 years old. The findings of this study suggest that there is no statistically significant correlation between OS/6-mo-PFS and age, sex, tumor type, type of treatment and relapse. Conclusions: The administration of combination Irinotecan-based regimen leads to a high response rate and low toxicity in some types of primary pediatric brain tumors especially embryonal tumors, while it has little effect on others such as astrocytoma and ependymoma.