Hepatocellular carcinoma (HCC) represents an estrogen-dependent tumor. The action of estrogen is regulated via estrogen receptor (ER). Polymorphisms in ERα gene, ESR1, are known to be related to HCC susceptibility among people carrying chronic hepatitis B (CHB). But the effect of ERβ on HCC is still largely unclear, and studies about the genetic variability of ESR2 and HCC are rare. For understanding ESR2's effect on HCC, this work tested two polymorphisms in the ESR2 gene promoter as well as the associations with CHB, HCC, and hepatitis B virus (HBV)-related liver cirrhosis (LC) among the Guangxi population. This work enrolled a total of 137 CHB, 136 LC, and 149 HBV-related HCC patients, together with 146 normal subjects. ESR2 polymorphisms rs3020449 and rs2978381 were examined using the SNaPshot genotyping technique. The AG genotype and dominant model of rs3020449 were related to the decreased CHB susceptibility. In both the overall and subgroup analyses, no associations were observed with the remaining models in all patient groups (those with CHB, HBV-related LC, and HCC), but associations were found between the dominant (TC+CC vs TT) and allele models (C vs T) of rs2978381 and increased HBV-related LC and HCC susceptibility, but not CHB. These findings suggest that rs3020449 polymorphism of ESR2 gene makes great contribution to the decreased CHB risk and that rs2978381 significantly contributed to higher risks of HBV-related LC and HCC.