Previous studies have demonstrated that hypoxia-inducible factor-1a (HIF-1a) may play a vital role in the pathogenesis of hepatocellular carcinoma (HCC). However, the relationship between HIF-1a polymorphisms and HCC has not been thoroughly investigated. The aim of this study is to determine whether HIF-1a polymorphisms are associated with HCC through a case-control study. Two polymorphisms in the HIF-1a gene (rs11549465 and rs115494657) were examined in 157 hepatitis B virus (HBV)-related HCC patients and 173 healthy controls using the polymerase chain reaction-restriction fragment length polymorphism method. DNA sequencing was used to validate genotype results. There were no significant differences in the genotype and allele frequencies of HIF-1a rs11549465 and rs115494657 polymorphisms between the HBV-related HCC patients and healthy controls. However, the data revealed that subjects with the CG haplotype have a higher susceptibility to HBV-related HCC [odds ratio (OR)=2.327, 95% confidence interval (CI)=1.578-4.721, P=0.008]. In contrast, the CA haplotype was associated with a significantly decreased risk of HBV-related HCC (OR=0.416, 95% CI=0.172-0.910, P=0.025). HIF-1a rs11549465 and rs115494657 polymorphisms appeared to be irrelevant to HBV-related HCC. However, the HIF-1a CG and CA haplotypes might be a risk factor and a protective marker, respectively, for HBV-related HCC in a Chinese population. Further investigations with a larger sample size may be required to validate the genetic effects of HIF-1a polymorphisms on HBV-related HCC.