Background: The Cytokine Receptor-Like Factor 2 (CRLF2) genes play an important role in early Bcell development. Aberrations in CRLF2 activate the JAK-STAT signaling pathway that contributes to B-cell Acute Lymphoblastic Leukemia (B-ALL). The prognostic significance of CRLF2 overexpression in various B-ALL risk subgroups has not been well established. Methods: Thirty patients with newly diagnosed childhood B-ALL were enrolled from the Egyptian population. All the patients in this study were assessed by detailed history taking, a complete clinical examination required radiological and routine laboratory investigations, and flow cytometry to detect the subtype of ALL. Peripheral Blood and bone marrow samples were taken from patients, and the CRLF2 expression was measured using RT-PCR. Results: The prevalence of CRLF2 overexpression status was analyzed, and the prognostic impact of CRLF2 overexpression on B-ALL was evaluated by assessing their influence on overall survival and event-free survival. CRLF2 overexpression was found in 56% of the whole cohort. The results showed that CRLF2 overexpression was associated with a poor outcome in unselected B-ALL. Conclusion: From the present study's findings, we can conclude that CRLF2 gene expression at diagnosis has a significant prognostic impact on the clinical outcome in childhood ALL.