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Although tobacco smoking is the primary risk factor for lung cancer, low dietary folate intake and suboptimal DNA repair capacity also contribute to lung cancer risk. Thymidylate synthase (TYMS) is involved in the metabolism of folate and the provision of nucleotides needed for DNA synthesis and repair. Thus, a variation in TYMS functions likely plays a role in the etiology of lung cancer. The TYMS gene has a tandem repeat polymorphism (two or three 28 bp) in the TYMS enhancer region (TSER) and a 6 bp deletion/insertion polymorphism in the TS 3′-untranslated region (TS3′UTR or 1494del6). We investigated the frequencies of these two polymorphisms in a hospital-based case–control study of 1055 lung cancer patients and 1140 cancer-free controls in a non-Hispanic white population and genotyped for these two polymorphisms. We found that the TS3′UTR, but not the TSER, variant was associated with the risk of lung cancer. Compared with homozygotes for the TS3′UTR 6 bp deletion (0bp/0bp), the 6bp/0bp+6bp/6bp genotypes were associated with a significantly increased risk of lung cancer [odds ratio (OR) = 1.52, 95% confidence interval (CI) = 1.12–2.06]. In stratification analysis the risk associated with the 0bp/6bp+6bp/6bp genotype was more pronounced in subjects who were >55 years old (OR = 1.57, 95% CI = 1.10–2.23), males (OR = 1.88, 95% CI = 1.22–2.89), current (OR = 2.04, 95% CI = 1.26–3.29) and heavy smokers (OR = 1.73, 95% CI = 1.10–2.70) and current drinkers (OR = 3.17, 95% CI = 1.78–5.64).Furthermore, significant gene–dietary interactions were found between TS3′UTR and alcohol consumption and between TSER and vitamin B12 intake. In conclusion, the polymorphisms of TYMS are likely to contribute to the risk of lung cancer in non-Hispanic whites and interact with dietary factors in lung cancer development.