Acute lymphoblastic leukemia (ALL) is the major pediatric cancer in developed countries. The etiology of ALL remains poorly understood, with few established environmental risk factors. These risks were influenced by co-inheritance of multiple low-risk genetic polymorphisms such as variants within cytochrome P450A1 (CYP1A1), NADPH: quinone oxidoreductase (NQO1) and Thiopurine methyltransferase (TPMT) genes. In this work, we conduct a case-control study to assess the impact of CYP1A1*2A (CYP1A1 T6235C); NQO1*2 (NQO1 C609T); TPMT*2 (TPMT G238C) and TPMT A719G polymorphisms on the risk of developing ALL. The frequencies of TPMT*2, TPMT A719G, NQO1*2 and CYP1A1*2 variants were examined in 100 patients with ALL and 106 healthy controls by allele specific PCR and/or PCR-RFLP methods using blood samples. We have found that NQO1 609CT genotype was overrepresented in patients and was associated with an aggravating effect compared to the reference group with NQO1 609CC genotype (p = 0.028, OR = 1.41; CI 95 %: 1.04-1.93). However, TPMT*2, TPMT 719*G and CYP1A1*2 variants did not appear to influence ALL susceptibility (p > 0.05). Moreover we have not found a significant correlation between the studied variants and Bcr-Abl transcript. In conclusion we retain that leukemogenesis of ALL is associated with carcinogens metabolism and consequently related to environmental exposures.