Aim: Previous research has suggested that Ephrin receptor A3 (EphA3) plays signaling roles in the processes of inflammation by regulating lymphocyte migration and proliferation. In this study, we investigated whether the EphA3 gene polymorphism was associated with disease progression of chronic hepatitis B virus (HBV) infection. Methods: The EphA3 variant rs9310117 was genotyped in 1245 unrelated Han Chinese HBV carriers including 800 cases and 445 controls. ?2 test was used to examine the difference in allele frequencies and genotype distributions between groups. The association between the polymorphism and disease progression of HBV infection was conducted by unconditional logistic regression analysis. Results: Statistical analysis revealed that the genetic variant was significantly associated with the occurrence of chronic severe hepatitis B (CSHB). We observed that subjects bearing at least one T allele (C/T or T/T genotype) had a decreased susceptibility to chronic severe hepatitis B compared with those bearing C/C genotype (P = 0.003, odds ratio = 0.560; 95% confidence interval, 0.3810.824, recessive model). Genotype C/T had also been confirmed to protect subjects from suffering chronic severe hepatitis B (P = 0.001, odds ratio = 0.498; 95% confidence interval, 0.3300.752, additive model). Conclusion: Our results suggest that the genetic alteration at EphA3 locus plays a role in the occurrence of chronic severe hepatitis B.