To evaluate the relationship between polymorphisms (28 bp repeated sequences in 5’-UTR and 6-bp ins/del in 3’-UTR) in then thymidylate synthetase gene (TS) and risk of colorectal, colon and rectal cancers, weconducted a case-control study with 315 cases of colorectal cancer and 439 population-based controls in Jiangsuprovince, China. TS genotypes were identified using PCR–RFLP (restriction fragment length polymorphism)methods. Odds ratios (ORs) were estimated with an unconditional logistic regression model. We found that thedistributions of 5’-UTR genotypes in TS were significantly different between controls and male colon cases (χ2=8.25, P = 0.016). Compared with 3R/3R genotype, individuals with the 2R allele were at an increased risk ofcolon cancer (age-, BMI-, smoking- and alcohol drinking-adjusted OR=1.98, 95%CI: 1.11-3.53) among men. Inccontrast, the 6-bp ins/del polymorphism at the TS 3’- UTR did not influence risk of the colorectal, colon andrectal cancers. When combined genotypes for both TS 5’-UTR and 3’-UTR polymorphisms were evaluated,individuals with the 5’-UTR 2R allele had a OR of 3.61 (95%CI: 1.38-9.49) for colon cancer among men withthe 3’-UTR –6bp/-6bp genotype. These results show that the polymorphism of the 28 bp repeated sequences inTS 5’-UTR could influence susceptibility to colon cancer and that there was a coordinated effect between TS3’-UTR and 5’-UTR polymorphisms in increasing risk of colon cancer among Chinese men.