BACKGROUND AND AIMS: Homozygosity for the thermolabile variant of 5,10-methylene tetrahydrofolate reductase (C677T) has been suggested to be positively associated with the risk of vascular disease and neural tube defects. In addition, recent studies have suggested that elevated serum uric acid predicts ischemic heart disease, and epidemiological data on ethnic groups have suggested that genetic factors are determinants of serum uric acid levels. In this study, we tested the hypothesis that 5,10-methylenetetrahydrofolate reductase (C677T) polymorphism may be associated with hyperuricemia. METHODS AND RESULTS: Samples from 518 healthy individuals (268 men and 250 women) were analyzed for MTHFR genotyping and serum uric acid. The participants were categorized to homozygous wild type (CC), heterozygous for wild type and thermolabile (CT), or homozygous for the thermolabile (TT) variant. Serum uric acid was significantly higher in males and females with TT genotype than those with either CC or CT genotype (p=0.0001, ANOVA). Univariate and multivariate analysis showed that 5,10-methylenetetrahydrofolate reductase (C677T) polymorphism was a strong correlate and predictor of uric acid in males (r=0.28, p=0.0001, beta=0.673, p=<0.001) and in females (r=0.27, p=0.0001, beta=0.599, p=<0.001). Odds ratio analysis has also shown that the risk of hyperuricemia was greater in males (OR 3.1, CI 1.8-5.2, p=0.001) and females (OR 3.3, CI 1.9-5.7, p=<0.001) with CT genotypes and in males (OR 3.7, CI 1.3-10.7, p=0.014) and females (OR 3.2, CI 1.1-9.7, p=0.032) with TT genotypes than in those with CC genotypes. CONCLUSION: Results from this study suggest that mutation of 5-MTHFR C677T contributes to the higher uric acid levels in both males and females and may be a risk factor for hyperuricemia.