Abstract Background NAD (P) H: quinone oxidoreductase (1) (NQO1‐HGNC: 2874) and myeloperoxidase (MPO‐HGNC: 7218) are two enzymes involved in phase II of the xenobiotic metabolism pathway. Methods In this study, a case–control analysis was conducted to investigate the relationship between genetic variations in the NQO1 (C609T, rs1800566; IVS1‐27 C >G, rs689452) and MPO (G463A, rs2333227) genes and the risk for bladder cancer among Tunisian population. Results We have found that the MPO 463GA genotype was associated with a decreased risk of developing bladder cancer (p = 0.049; OR = 0.696; 95% CI 0.484–0.999). In contrast, we have found that the NQO1 609CT genotype could increase the risk of bladder cancer patients (p = 0.0039; OR = 1.454; 95% CI = 1.017–2.078). Moreover, patients with “NQO1 609 CT/IVS1‐27 CG” genotype show a 2.180‐fold increasing risk for developing bladder cancer in comparison to the control group with wild genotype. This OR is estimated at 5.6‐fold in smokers patients with “NQO1 609 CT/IVS1‐27 CG” genotype. Lastly, study findings suggest that the NQO1 IVS‐27 *CG genotype (rs689452) is associated with a risk of progression to muscle invasive bladder cancer. Conclusion Our study suggests that environmental risk factors in association to NQO1 genotypes (NQO1 609 CT/IVS1‐27 CG) play an important role in the development of bladder cancer in Tunisian population.
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