Genetic factors may contribute to individual differences in cancer susceptibility. This study was designed to investigate the effects of the polymorphisms of methylenetetrahydrofolate reductase 677 C → T (MTHFR 677 C → T), methylenetetrahydrofolate reductase 1298 A → C (MTHFR 1298A → C), thymidylate synthase (TYMS 3R → 2R), and methionine synthase 2756 A → G (MTR 2756 A → G) on the risk of primary liver cancer (PLC). We conducted a case-control study involving 356 PLC cases and 641 healthy controls in North China. Compared with the MTHFR 677CC genotype, the MTHFR 677TT genotype showed an increased risk for PLC (TT vs. CC: adjusted odds ratio (OR) = 1.56; 95% confidence interval (CI): 1.02-2.40; P = 0.043) after adjusting for gender and age, whereas the MTHFR 1298CC genotype showed a significantly decreased risk for PLC (CC vs. AA: adjusted OR = 0.23; 95% CI: 0.08-0.70; P = 0.010). However, no significant association was found between the TYMS 3R → 2R or the MTR 2756 A → G polymorphism and the risk of PLC. Our results suggest that the MTHFR 677 C → T and the MTHFR 1298A → C genetic polymorphisms might play important role in hepatic carcinogenesis. Further studies with larger sample sizes are required to validate this association.