Background: Tumor necrosis factor-alpha (TNF-alpha) is a pro-inflammatory cytokine that may act as an endogenous tumor promoter. A genetic polymorphism of TNF-alpha gene at position -308 promoter region is involved in the regulation of expression level and has been found to be associated with susceptibility to various types of cancer. Methods: To determine the association of the TNF-alpha gene G-308A polymorphism on the risk of hepatocellular carcinoma (HCC) in a Turkish population, a hospital-based case-control study was designed consisting of 110 diagnosis subjects with hepatocellular carcinoma and 110 cancer-free control subjects matched on age, gender, smoking and alcohol status. The genotype frequency of this polymorphism was determined by using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Results: The distribution G-308A genotype was significantly associated with the risk of HCC (p < 0.001, odds ratio [OR] = 4.75, 95% confidence interval [CI] = 2.25-9.82 for -308 AA/GA genotypes versus GG genotype). Conclusion: We suggested that the presence of the high producer allele -308A in the TNF-alpha gene appears to be associated with an increased risk for the development of HCC in Turkish population. Published by Elsevier Ltd.