Objective To evaluate the relationship between estrogen receptor- α- 29( ERα- 29) gene polymorphisms and the development of HBV- related hepatocellular carcinoma( HCC) in Gansu Province,China,and to investigate the pathogenesis of HCC at the gene level. Methods Gene polymorphisms of ERα- 29 were analyzed in 106 HBV- related HCC patients and 98 healthy individuals as normal controls using the polymerase chain reaction- restriction fragment length polymorphism technique. Population allele frequencies were calculated using the gene counting method and then tested using the Hardy- Weinberg law of genetic equilibrium. Comparisons of genotype and allele frequencies between groups were performed using the χ2test. Results The frequencies of TT genotype and T allele of ERα- 29 gene in HBV- related HCC patients were significantly higher than those in the normal controls,i. e.,31. 1% and 53. 8% vs. 11. 2% and 32. 1%( χ2= 3. 449,P < 0. 05; χ2= 3. 840,P < 0. 05). In contrast,the frequencies of CC genotype and C allele of ERα- 29 gene in HBV- related HCC patients were significantly lower than those in the normal controls,i. e.,23. 6% and 46. 2% vs. 47. 0% and 67. 9%( χ2= 3. 488,P <0. 05; χ2= 3. 840,P < 0. 05). Compared with those carrying C allele,carriers of T allele had an increased risk( 2. 46- fold) of HBV- related HCC( OR = 2. 46,95% CI: 1. 64- 3. 69). Conclusion T allele of ERα- 29 gene can increase the risk of HBV- related HCC.