Objective To investigate the distribution of the single nucleotide polymorphism (SNP) of-251 (rs4073) in cytokine interleukin 8 gene promoter region and +781 (rs2227306) in the first intron in Nantong area population, to explore the correlation between the genotypes of these sites and the risk of suffering hepatocellular carcinoma (HCC), and to analyze the interaction between the genotypes and different exposure factors inducing the occurrence of HCC. Methods By using case-control study and restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR) technique, the genotypes of IL-8 gene-251 site and+781 site were classified. Results (1) In individuals with-251 heterozygous mutation genotype AT the risk of developing HCC increased (OR=1.99, 95%CI: 1.01-3.85), and in individuals with +781 mutation genotype CT and TT the risk of developing HCC increased (+781 CT genotype, OR=1.78, 95%CI:1.03-3.1; +781 TT genotype, OR=1.36, 95%CI: 1.01-2.62). (2) In individuals with -251 and +781 AT-CT, TT-CT, AT-CC combined genotypes the risk of developing HCC increased (AT-CT combined genotype, OR=2.10,95%CI:1.52-2.9;TT-CT combined genotype, OR=3.33, 95%CI: 1.01-10.50; AT-CC combined genotype, OR=3.67, 95%CI:2.28-5.90). (3)SNP of-251 had positive interactions with drinking, HBV infection and family history of HCC in the occurrence of HCC, while negative interactions existed between SNP of this site and exposure factors, including age, gender and smoking, in the occurrence of HCC. SNP of +781 had positive interactions with drinking and family history of HCC in the occurrence of HCC, while negative interactions existed between SNP of this site and exposure factors, including age, sex, smoking and HBV infection, in the occurrence of HCC. Conclusion Definite correlation exists between SNP of -251,+781 sites in interleukin 8 gene and the risk of the occurrence of HCC in Nantong area population;and there are interactive effects between SNP of -251, +781 sites in interleukin 8 gene and several exposure factors.