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Background: Relapse is the main reason of treatment failure in childhood acute Lymphoblastic leukemia (ALL). Aim: To study the treatment outcome of first ALL relapse in response to two different reinduction regimens and prognostic factors predicting outcome. Methods: A retrospective study that included 82 children with ALL in the 1st relapse from two tertiary oncology centers in Upper Egypt. Patients were treated according to the St. Jude ALL-R16 protocol. Seventeen patients were treated with a standard reinduction (regimen 1) and 65 were treated with a modified reinduction regimen in which anthracycline was added and asparaginase was reduced to 9 doses (regimen 2). Response, survival and prognostic factors were analyzed. Results: Second, complete remission (CR2) was achieved in 57% of all patients (65% with regimen 2 vs. 29% with regimen 1, p = 0.009). FLAG regimen resulted in achieving CR2 in all patients with reinduction failure. Treatment related mortality was more common with regimen 2 than with regimen 1 (34% vs. 12%, respectively). For all patients, the 2-year overall and event-free survival rates were 30% and 25%. In multivariate analysis, high initial total leukocytic count, isolated medullary relapse, regimen 1 and very early relapse were independently associated with worse event free survival (p = 0.031, 0.017, 0.037 and 0.001; respectively). Conclusions: The overall outcome of treatment of first ALL relapse in children in our region is poor. New intensive chemotherapy regimens may help in improving the treatment outcome. [ABSTRACT FROM AUTHOR]