Korea has the highest incidence of thyroid cancer of any nation. We conducted a population-based, case-control study of the association between the risk of papillary thyroid cancer (PTC) in the Korean population and polymorphisms of methylenetetrahydrofolate reductase (MTHFR) C677T, glutathione S-transferase class mu (GSTM1), and glutathione S-transferase class theta (GSTT1). The study subjects consisted of 2,194 newly diagnosed PTC cases and 1,669 population-based healthy controls. Odds ratios adjusted by age, sex, body mass index, smoking, drinking, serum thyroid-stimulating hormone level, family history of thyroid cancer, and previous history of thyroid disease, with 95% confidence intervals, were estimated using logistic regression analysis. The frequencies of MTHFR 677TT genotypes, and null genotypes of GSTM1 and GSTT1 were 19.2, 56.8, and 51.4% among PTC cases and 17.4, 54.1, and 50.6% among the controls, respectively. No significant associations between PTC and TT genotypes of MTHFR C677T, null genotypes of GSTM1 and GSTT1, or double-null (GSTM1-GSTT1) genotypes were found. These findings suggest that polymorphisms of the MTHFR C677T, GSTM1 and GSTT1 genotypes do not contribute to the development of PTC susceptibility in the Korean population.