Single nucleotide polymorphisms (SNPs) of HLA-DQ and granulysin (GNLY) are reportedly associated with HBV infection. The aim of this study was to investigate the effects of interactions between SNPs in HLA-DQ and GNLY on the outcome of hepatitis B virus (HBV) infection in Chinese Han subjects. HLA-DQ (rs9275572) and GNLY (rs1866139 and rs11127) were genotyped in 310 subjects with HBV-related chronic liver disease, 295 in whom spontaneous clearance of HBV had occurred and 316 who had not been exposed to HBV. HLA-DQ rs9275572 was significantly correlated with HBV clearance (dominant genetic model: OR, 1.84; 95% CI, 1.30–2.61; adjusted P = 0.001). There was no statistical association of GNLY rs1866139 and rs11127with HBV infection outcomes. However, significant sex-specific associations with HBV susceptibility were observed in men who carried rs1866139 CG or rs11127 TC and in women who carried rs1866139 GG or rs11127 CC. The findings were the same in the validation cohort, which was composed of 829 subjects. Based on a multifactor dimensionality reduction test with permutation correction, a three-way interaction between SNPs in HLA-DQ and GNLY was identified in terms of HBV clearance. In conclusion, additional evidence for an association of HLA-DQ and GNLY SNPs with HBV infection outcomes has been identified and a SNP-SNP interaction between HLA-DQ and GNLY on HBV clearance observed.