Abstract: Objective To explore the association of interleukin-2(IL-2)-330T/G (rs2069762),interferon gamma (IFN-γ)-1615C/T(rs2069705) and +5171A/G(rs2069727) single nucleotide polymorphisms(SNPs) with the incidence of primary hepatocellular carcinoma(HCC),and to provide the reference for HCC risk assessment.Methods A hospital-based case-control study was carried out.Totally 784 HCC patients from First Affiliated Hospital of Guangxi Medical University and Guangxi Cancer Hospital and 1 017 controls from Physical Examination Center of First Affiliated Hospital of Guangxi Medical University and Guangxi People's Hospital were investigated with a environmental exposure questionnaire during June 2007-July 2010.TaqMan fluorescence quantitative PCR technology was adopted to detect the SNPs of the genes.The interactions of gene-environment and gene-gene w ere analyzed with logistic regression model.Results -1615C/T and +5171A/G of IFN-γ had linkage disequilibrium (D'=0.976,r²=0.549,P=2.22^-16).The frequency of haplotype CG was less than 0.03 in the study population.CA,TA and TG had no statistically significant difference among the three groups(P > 0.05).There were no statistically significant differences in the polymorphisms of IL-2 -330T/G,IFN-γ-1615C/T and +5171A/G between HCC patients and controls(P > 0.05).The interactions of IL-2330T/G mutant allele G with smoking,alcohol drinking and carrying HBV were positive with the synergy indexes(S) of 1.38,1.50,and 1.03,respectively.The individuals carrying IL-2-330T/G mutant gene G and both IFN-gamma-1615C/T and +5171A/G mutant homozygote(TT and GG) had increased risk of HCC(odds ratio=1.84,95% confidence interval:1.08-3.83).Conclusion There are interactions among polymorphisms of IL-2-330T/G and IFN-γ-1615C/T,+5171A/G and the environmental exposure.The gene-environment and gene-gene interaction may increase the risk of HCC.