NAD (P) H: quinone oxidoreductase 1 (NQO1) protects cells against oxidative stress and toxic quinones. NQO1 was reported associated with many malignancies, especially hematological malignancies. This study aims at evaluating the presence of NQO1 polymorphism in acute leukemia patients. Subject and methods: 30 de novo cases of acute leukemia (15 AML and 15 ALL), in addition to 20 apparently healthy individuals as control, were evaluated regarding the NQO1 genotype. Results: NQO1 mutation was reported in 22 patients (73.3%) were homozygote for wild type allele (CC) and 8 patients (26.7%) showed abnormal genotype: 7 patients (23.3%) were heterozygote (CT)«one gene is mutant and other is normal gene» and 1 patient (3.3%) was homozygote for mutant allele (TT). It was associated with poor prognosis .No significant correlation was found with clinical signs relevant to leukemia as liver, spleen; lymph node infiltration shows no significant association with NQO1 polymorphism. . CNS infiltration was significantly higher in ALL patients with NQO1 polymorphism. Conclusion: Null or low NQO1 activity caused by inheritance of one or more mutant C609T alleles is associated with increased risk of de novo acute leukemia.