Exonuclease 1 (Exo 1) is an important nuclease involved in the mismatch repair system that contributes to maintaining genomic stability, modulating DNA recombination and mediatingcell cycle arrest. A cytosine (C)/thymine (T) common single nucleotide polymorphism (SNP) at second position of codon 439 in exon 10 of Exo 1 determines a threonine (Thr, T) to methionine (Met, M) (T439M) aminoacidic substitution which may alter cancer risk by influencing the activity of Exo 1 protein. The association of Exo 1 T439M polymorphism with hepatocellular carcinoma (HCC) susceptibility has yet to be investigated. To assess this possibility in a Turkish population, a hospital-based case-control study was designed consisting of 224 subjects with HCC and 224 cancer-free control subjects matched for age, gender, smoking and alcohol status. The genotype frequency of the Exo 1 T439M polymorphism was determined by using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. No statistically significant differences were found in the allele or genotype distributions of the Exo 1 T439M polymorphism among HCC and cancer-free control subjects (P>0.05). Our result demonstrates for the first time that the Exo 1 T439M polymorphism does not have a major role in genetic susceptibility to hepatocarcinogenesis, at least in the population studied here. Independent studies are need to validate our findings in a larger series, as well as in patients of different ethnic origins.