Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. It constitutes a major health problem in both developed and developing countries. In Egypt,the incidence of HCC is remarkedly increasing because of the high prevalence of hepatitis C viral infection. In this study, we investigated whether methylenetetrahydrofolatereductase (MTHFR) C677T polymorphism has a role in the development of HCC in Egyptians. We recruited 128 patients diagnosed with HCC from the Hepatology and Gastroenterology Department, Mansoura Specialized Medical Center, MansouraUniversity Hospitals at the Delta region of Egypt. In addition, a total of 130participants who were confirmed as having hepatitis C viral infection constituted the other group in this study. The genotypes and allele distributions in both groups were investigated using PCR-RFLP and were compared. On comparing the frequency of alleles, genotypes in two patient groups revealed statistical significance for MTHFRC677T gene polymorphism in HCC patients. The CT and TT genotype and the T allele of MTHFR C677T gene polymorphism all showed a significant risk of developing HCC [odds ratio (OR)=1.92; 95% confidence interval (CI)=1.11–3.32; P=0.019; (OR=4.91; 95% CI=1.32–18.24; P=0.018); (OR=2.113; 95% CI=1.36–3.29; P=0.001), respectively].