Background: The recognition of central nervous system (CNS) involvement at the time of diagnosis in acute lymphoblastic leukemia (ALL) is crucial for determining appropriate treatment strategies and reducing the risk of CNS relapse. While CNS involvement at diagnosis is relatively rare, occurring in less than 5% of children and 10% of adults with ALL, it remains an important consideration due to its potential impact on prognosis.Materials and methods:In the retrospective analysis of 102 patients with acute lymphoblastic leukemia (ALL) and CNS relapse, the study aimed to compare clinical, hematological, phenotypical, and molecular features at the time of diagnosis and response to treatment between patients with isolated CNS relapse (Group 1) and those with combined CNS relapse with concurrent bone marrow relapse (Group 2). Additionally, the study aimed to identify risk factors associated with relapse in these patients. Results: Among 720 patients with acute lymphoblastic leukemia (ALL), 102 (14.17%) experienced CNS relapse. Median blast percentage in peripheral blood was 55%. Hyperleucocytosis seen in 26.47% patients and peripheral smear blasts >50% in 50.98%. Immunophenotyping revealed that 13.73% of cases were T-cell ALL, while 83.33% were B-cell ALL. Philadelphia chromosome identified in 15.69% cases. Among patients with CNS relapse, 33.33% experienced isolated CNS relapse, while 66.67% had concurrent bone marrow relapse. Patients in Group 2 were more likely to present with hyperleukocytosis and peripheral smear blasts >50% compared to those in Group 1. Conclusion: In our study we found hyperleucocytosis and TLC at time of relapse were significantly associated with CNS relapse