The non-classical human leukocyte antigens (HLA)-E, HLA-G, and HLA-F have been shown to modulate immune responses. We examined whether non-classical HLA polymorphisms are associated with hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). Fifteen Single-nucleotide polymorphisms (SNPs) in these non-classical class I alleles were investigated by ligase detection reaction. A fragment of 650 bp located in the 3' untranslated region of HLA-G was investigated. Four SNPs (rs17875380, rs41557518, rs114465251, and rs115492845) were associated with altered susceptibility to HBV or HCC, and HLA-F*01:04, HLA-G*01:05N, and HLA-E*01:01 were associated with hepatitis B or hepatitis B complicated with HCC. Six of 16 designated HLA-E, -G, and -F haplotypes were associated with risk of hepatitis B or HCC. Our study provides healthy reference and detailed analyses of non-classical HLA class Ι polymorphisms that provide insight into immune mechanisms involved in susceptibility to hepatitis B and HCC.