To assess the contribution of tumor necrosis factor (TNF)β +252 polymorphisms to risk and prognosis ofhepatocellular carcinoma (HCC), we enrolled 150 pairs of sex- and age-matched patients with HCC, patientswith cirrhosis alone, and unrelated healthy controls. TNFβ +252 genotypes were determined by polymerasechain reaction with restriction fragment length polymorphism. Multivariate analysis indicated that TNFβ G/Ggenotype [odds ratio (OR), 3.64; 95%CI, 1.49-8.91], hepatitis B surface antigen (OR, 16.38; 95%CI, 8.30-32.33),and antibodies to hepatitis C virus (HCV) (OR, 39.11; 95%CI, 14.83-103.14) were independent risk factors forHCC. There was an additive interaction between TNFβ G/G genotype and chronic hepatitis B virus (HBV)/HCVinfection (synergy index=1.15). Multivariate analysis indicated that factors associated with TNFβ G/G genotypeincluded cirrhosis with Child-Pugh C (OR, 4.06; 95%CI, 1.34-12.29), thrombocytopenia (OR, 6.55; 95%CI,1.46-29.43), and higher serum α-fetoprotein concentration (OR, 2.53; 95%CI, 1.14-5.62). Patients with TNFβG/G genotype had poor cumulative survival (p=0.005). Cox proportional hazard model indicated that TNFβ G/Ggenotype was a biomarker for poor HCC survival (hazard ratio, 1.70; 95%CI, 1.07-2.69). In conclusion, thereare independent and additive effects between TNFβ G/G genotype and chronic HBV/HCV infection on risk forHCC. It is a biomarker for poor HCC survival. Carriage of this genotype correlates with disease severity andadvanced hepatic fibrosis, which may contribute to a higher risk and poor survival of HCC. Chronic HBV/HCVinfected subjects with this genotype should receive more intensive surveillance for early detection of HCC.