It is well known that high serum uric acid (SUA) is the cause of gout and a risk factor of cardiovascular diseases. Although SUA is thought to have an association with folate metabolism through elevated production and/or damaged renal excretion, studies on functional polymorphisms of folate metabolizing are still limited, showing inconsistent findings. We hypothesized that hyperuricemia would be associated with methylenetetrahydrofolate reductase (MTHFR) C677T and thymidylate synthase (TS) 28-bp tandem repeat polymorphism. Subjects were 793 healthy health checkup examinees (272 male and 521 female Japanese) aged 39 years or older. There was no clear difference in SUA means among those with different genotypes of MTHFR and TS, but a significant association between hyperuricemia (SUA > or =7mg/dL) and MTHFR 677T allele carriers was observed. The odds ratio of harboring 677T allele adjusted for sex, age, body mass index, serum creatinine, systolic blood pressure, currents habits of smoking and drinking, and TS genotype was 2.77 (95% confidence interval, 1.38-5.56). The TS genotype was not significantly associated with hyperuricemia; the corresponding adjusted odds ratio was 1.36 (95% confidence interval, 0.75-2.48) for non-33 genotype relative to 33 genotype. Because MTHFR 677CC was rarer both in <4 mg/dL group and > or =7 mg/dL group, the comparisons of SUA means were not useful to elucidate the roles of the polymorphism. This new view may partly explain the inconsistent results on the association of the MTHFR polymorphism with SUA.