Objective To investigate the genetic polymorphisms of PD-1 and CTLA-4 3′UTR in chronic HBV infection and the interaction between the two. Methods Through the case-control study method, PCR-RFLP technology was used to detect 433 chronic HBV infections and 208 healthy controls. The genotype distribution frequency of PD-1 rs10204525 and CTLA-4 rs3087243 was used to analyze the HBV infection group and health by 2 test. The relationship between genotype frequency, allele frequency, gene interaction, and disease severity in the control group. Results PD-1 rs10204525:compared with the GG genotype, the frequency of the AA genotype in the chronic HBV infection group was significantly higher than that in the healthy control group (P=0.019, OR=2.231, 95%CI=1.127-4.418), A allele The gene frequency was significantly higher than that of the healthy control group (P=0.033, OR=1.334, 95%CI=1.024-1.739). CTLA-4 rs3087243: compared with the AA genotype, the frequency of the GG genotype in the chronic HBV infection group was significantly higher than that in the healthy control group (P=0.016, OR=2.196, 95%CI=1.145-4.214), and the G allele frequency It was significantly higher than the healthy control group (P=0.040, OR=1.320, 95%CI=1.012-1.723). After the genotype interaction of PD-1 and CTLA-4, the differences between the HBV infection group and the healthy control group, the severity of the disease, and the relationship with liver cancer were statistically significant.Conclusion The AA genotype and A allele of PD-1 rs10204525 may be risk factors for chronic HBV infection, and the GG genotype and G allele of CTLA-4 rs3087243 may be risk factors for chronic HBV infection. Combined genotype can increase the risk factors of chronic HBV infection. The GG genotype and G allele of CTLA-4 rs3087243 may be related to HCC infection.