The single nucleotide polymorphism (SNP) rs1053004 in Signal transducer and activator of transcription 3 (STAT3) was recently reported to be associated with chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC) in a Chinese cohort. This study was aimed at investigating whether the SNP might also contribute to HCC susceptibility in the Thai population. Study subjects were enrolled and divided into 3 groups including CHB-related HCC (n=211), CHB without HCC (n=233) and healthy controls (n=206). The SNP was genotyped using allelic discrimination assays based on TaqMan real-time PCR. Data analysis revealed that the distribution of different genotypes was in Hardy-Weinberg equilibrium (P>0.05). The frequencies of allele T (major allele) in HCC patients, CHB patients and healthy controls were 51.4%, 58.6% and 61.4%, respectively, whereas the frequencies of C allele (minor allele) were 48.6%, 41.4% and 38.6%. The C allele frequency was higher in HCC when compared with CHB patients (odds ratio (OR)=1.34, 95% confidence interval (CI)=1.02-1.74, P=0.032). The genotype of SNP rs1053004 (CC versus TT+TC) was significantly associated with an increased risk when compared with CHB patients (OR=1.83, 95% CI=1.13-2.99, P=0.015). In addition, we observed a similar trend of association when comparing HCC patients with healthy controls (OR=1.77, 95% CI=1.07-2.93, P=0.025) and all controls (OR=1.81, 95% CI=1.19-2.74, P=0.005). These findings suggest that the SNP rs1053004 in STAT3 might contribute to HCC susceptibility and could be used as a genetic marker for HCC in the Thai population.