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Lymphotoxin-β receptor (LTβR) signaling is involved in hepatitis B virus (HBV) infection, hepatitis and liver carcinogenesis. However, the potential association between LTBR polymorphisms and HBV infection remains unclear. This study investigated the associations between LTBR polymorphisms and chronic HBV infection and HBV-related hepatocellular carcinoma (HCC). The study included 409 patients with chronic HBV infection, 73 HBV infection resolvers, and 197 healthy controls. Two polymorphisms rs12354 and rs3759333 were selected and genotyped by polymerase chain reaction-ligase detection reaction method. The frequencies of rs12354 genotype GT and allele T in HBV infection resolvers were significantly higher than those in patients with chronic HBV infection and healthy controls (genotype GT: 38.4% vs. 22.2% and 38.4% vs. 20.8%, P = 0.004 and P = 0.004, respectively; allele T: 20.5% vs. 13.1% and 20.5% vs. 12.9%, P = 0.017 and P = 0.028, respectively). The frequencies of rs3759333 genotypes and alleles between HBV patients, HBV infection resolvers and healthy controls had no statistical difference. The genotype and allele frequencies of rs12354 and rs3759333 had no statistical differences between chronic hepatitis B and HBV-related HCC patients. The serum LTβR levels and the overall survival rate between HBV-related HCC patients carrying different rs12354 and rs3759333 genotypes had no statistical differences. These results suggest that the LTBR rs12354 polymorphism might be associated with the spontaneous resolution of HBV infection. Additional studies with large sample size are needed to confirm and extend these findings.This study examined LTBR rs12354 and rs3759333 polymorphisms in chronic HBV infection.HBV chronically infected patients, infection resolvers, and healthy controls were included.There was a significant increase of rs12354 allele T frequency in HBV infection resolvers.No significant difference in rs3759333 was observed between the study subjects.LTBR rs12354 might be associated with the spontaneous resolution of HBV infection.