Objective Cytochrome P450 2E1 (CYP2E1) is an important metabolizing enzyme involved in oxidative stress responses to benzene,a chemical associated with bone marrow toxicity and leukemia.We aimed to identify the CYP2E1 genetic biomarkers of susceptibility to benzene toxicity in support of environmental and occupational exposure prevention,and to test whether a model using immortal human lymphocytes might be an efficient tool for detecting genetic biomarkers.Methods Immortalized human lymphocyte cell lines with independent genotypes on four CYP2E1 SNP sites were induced with 0.01% phenol,a metabolite of benzene.CYP2E1 gene function was evaluated by mRNA expression and enzyme activity.DNA damage was measured by Single‐Cell Gel Electrophoresis (SCGE).Results Among the four SNPs,cells with rs2070673TT and rs2030920CC showed higher levels of CYP2E1 transcription and enzymatic activity than the other genotypes in the same SNP site.Cells with higher gene expression genotypes also showed higher comet rates compared with lower gene expression genotypes.Conclusion These results suggest that CYP2E1 rs2070673 and rs2030920 might be the genetic biomarkers of susceptibility to benzene toxicity and that the immortalized human lymphocytes model might be an efficient tool for the detection of genetic biomarkers of susceptibility to chemicals. Objective Cytochrome P450 2E1 (CYP2E1) is an important metabolizing enzyme involved in oxidative stress responses to benzene, a chemical associated with bone marrow toxicity and leukemia. We aimed to identify the CYP2E1 genetic biomarkers of susceptibility to benzene toxicity in support of environmental and occupational exposure prevention, and to test whether a model using immortal human lymphocytes might be an efficient tool for detecting genetic biomarkers. Methods Immortalized human lymphocyte cell lines with independent genotypes on four CYP2E1 SNPs sites were induced with 0.01% phenol, a metabolite of benzene. CYP2E1 gene function was evaluated by mRNA expression and enzyme activity. DNA damage was measured by Single-Cell Gel Electrophoresis (SCGE). Results Among the four SNPs, cells with rs2070673TT and rs2030920CC showed higher levels of CYP2E1 transcription and enzymatic activity than the other genotypes in the same SNP site. Cells with higher gene expression genotypes also showed high er comet rates compared with lower gene expression genotypes. Conclusions These results suggest that CYP2E1 rs2070673 and rs2030920 might be the genetic biomarkers of susceptible to benzene toxicity and that the immortalized human lymphocytes model might be an efficient tool for the detection of genetic biomarkers of susceptibility to chemicals.