Aim: To evaluate the association between the polymorphisms of the Ku80 gene and the risk of colorectal cancer in Central Taiwan. Materials and Methods: In this hospital-based case-control study, the association of Ku80 G-1401T rs828907, Ku80 C-319T rs11685387 and Ku80 intron 19 rs9288518 polymorphisms with colorectal cancer risk in a central Taiwanese population was investigated. In total, 362 patients with colorectal cancer and 362 age- and gender-matched healthy controls recruited from the China Medical Hospital in central Taiwan were genotyped. Results: A significantly different distribution was found in the frequency of the Ku80 G-1401T genotype, but not the Ku80 C-319T or intron 19 genotypes, between the colorectal cancer and control groups. The T allele Ku80 G-1401T conferred a significantly (p=0.0069) increased risk of colorectal cancer. As for Ku80 C-319T and intron 19 polymorphisms, there was no difference in distribution between the colorectal cancer and control groups. Gene interactions with smoking, but not with alcohol consumption, were significant for Ku80 G-1401T polymorphism. The Ku80 G-1401T GT and TT genotype in association with smoking conferred an increased risk of 2.537 (95% confidence interval=1.398-4.601) for colorectal cancer. Conclusion: These results provide the first evidence that the T allele of the Ku80 G-1401T may be associated with the development of colorectal cancer and may be a novel useful marker for primary prevention and anticancer intervention.