Purpose:Folate deficiency and reduced DNA repair capacity are established risk factors for squamous cell carcinoma of the head and neck(SCCHN). We hypothesized that polymorphisms of the thymidylate synthase(TYMS)gene,which regulates a key enzyme in folate metabolism required for DNA synthesis and repair, are associated with SCCHN risk. Experimental Design:In a hospital-based case-control study of 704 SCCHN cases and 1,085 controls, frequency matched by age,sex, nd ethnicity,we genotyped the TSER(thymidylate synthase in the 5'-untranslated enhanced region)and TS3ˊUTR(thymidylate synthase in the 3'-untrans-lated region) polymorphisms. Results: The TS3ˊUTR 0bp/0bp genotype was associated with a significantly decreased risk of SCCHN[adjusted odd ratio(OR)=0.67,95%confidence interval (CI)=0.47-0.94] compared with the 6bp/6bp genotype, but the TSER polymorphism had no main effect on risk of SCCHN. When we evaluated the two polymorphisms together by the number of protective alleles(the TSER 3R and TS3'UTR 0bp alleles), we found that the combined genotypes with four protective alleles(the TSER 3R3R and TS3'UTR 0bp/0bp) was associated with significantly decreased SCCHN risk (OR=0.60, 95%CI=0.37-0.98). In addition,the TS3ˊUTR 0bp genotypes were associated in an allele dose-dependent manner with a decreased risk of overall stage IV oral cancer (OR=0.84, 95%CI=0.52-1.34 for the 6bp/0bp genotype and OR=0.26, 95%CI=0.08-0.87 for the 0bp/0bp genotype; Ptrend=0.035). Conclusion: The TSER and TS3'UTR polymorphisms are associated with SCCHN risk. The TSER 3R and TS3ˊUTR 0bp alleles seemed to jointly protect against SCCHN. In particular, the 0bp allele seemed to protect against oral cancer progression.