Objective: To investigate the relationship between the polymorphism of CYP4F2 gene and the susceptibility of coronary artery disease (CAD) in the Tujia population in Enshi, Hubei, and the interaction of serum selenium level and CYP4F2 gene polymorphism in the occurrence of CAD. Methods: A total of 100 cases of CHD were selected from the Tujia population in Enshi, Hubei, and 100 healthy subjects cases were served as controls. The polymorphism of CYP4F2 gene was detected by PCR, and the serum selenium level was measured by hydride generation atomic fluorescence spectrometry. Results: The serum selenium level in the CAD group was significantly lower than that in the control group; the CYP4F2 gene rs1558139 was not significantly related to the risk of CAD, and the rs2108622 polymorphism was significantly related to the risk of CAD. The risk of CAD was increased in the patients carrying the CC genotype, and the rs1558135 polymorphism of CYP4F2 gene was closely related to the risk of CAD. Patients with the rs3093135 gene carrying allele A had a lower risk of CAD. Low serum selenium level and CYP4F2 rs2108622 CC genotype play a positive role in the occurrence of CAD. Conclusion: The serum selenium level is negatively correlated with CAD in Tujia ethic group in Enshi, Hubei, and there is a synergistic effect between the serum selenium level and the CYP4F2 rs2108622 CC genotype, which significantly increases the risk of CAD.