Previous studies have suggested that low folate intake is associated with increased risk of lung cancer. Methylenetetrahydrofolate reductase (MTHFR) is one of the enzymes involved in folate metabolism and is thought to influence DNA methylation and nucleotide synthesis. MTHFR is highly polymorphic, and the variant genotypes result in decreased MTHFR enzyme activity and lower plasma folate level. Therefore, we hypothesized that these variant genotypes may play a role in the etiology of lung cancer. To test this hypothesis, we investigated the association between two common MTHFR polymorphisms (C677T and A1298C) and risk of lung cancer in a nonpopulation- based case-control study of 550 histologically confirmed lung cancer cases and 554 healthy controls. The subjects were non-Hispanic whites, and the controls were frequency-matched to the cases by age (65 years), sex, and smoking status (ever or never). Folate intake and alcohol consumption were estimated from a selfadministered food-frequency questionnaire. The cases consumed significantly less folate (162mg/day/1000 kcal) than the controls did (172mg/day/1000 kcal; P 5 0.033). However, we found no evidence for an association between the MTHFR C677T and A1298C polymorphisms and risk of lung cancer in either all of the subjects or the low folate intake subgroup; nor did we find evidence for an interaction between these two MTHFR polymorphisms and dietary folate intake or alcohol use. In multivariate logistic regression analysis, the adjusted odds ratios and 95% confidence intervals for MTHFR C677T were 1.1 (0.8-1.4) for 677CT versus 677CC wild type and 1.1 (0.7-1.7) for 677TT versus 677CC, and for MTHFR A1298C, they were 1.0 (0.8-1.3) for 1298AC versus 1298AA wild type and 1.1 (0.7-1.8) for 1298CC versus 1298AA. These MTHFR enzyme activity of those with the 677CC wild-type genotype, whereas heterozygotes (677CT) have about 65% ofnormal enzyme activity (15). Up to 15% of the population is homozygous 677TT for the variant, which is associated with higher plasma homocysteine levels and reduced plasma folate levels (16). The second common MTHFR polymorphism, a glutamate to alanine (A3 C) change at position 1298, also influences the specific activity of the enzyme, homocysteine levels, and plasma folate concentration but to a lesser extent than the C677T polymorphism does (14). Previous studies (17) of colorectal cancer reported a significantly decreased risk of colorectal cancer associated with the 677TT genotype that was not observed among those with low folate intakes or serum levels. Recently, another study (18) reported that individuals with the MTHFR 677TT, 1298AC, and 1298CC genotypes have reduced risk of adult acute lymphocytic leukemia. However, the association between these two common MTHFR polymorphisms and the risk of lung cancer has not been examined. Because the MTHFR polymorphisms reduce enzyme activity and low dietary intake of folate is associated with increased risk of lung cancer, we hypothesized that the MTHFR polymorphisms are associated with risk of lung cancer. We tested this hypothesis by genotyping our specimens from a non-population-based case-control study of lung cancer for these two MTHFR polymorphisms.