The DNA repair gene X-ray repair complementing defective repair in Chinese hamster cells 4 (XRCC4) is thought to play a major role in the caretaking of the whole genome via double-strand break repair. However, the association of polymorphic variants of XRCC4 with colorectal cancer susceptibility has never been reported. In this hospital-based case-control study, the association of XRCC4 polymorphisms C-1622T (rs7727691), G-1394T (rs6869366), G-652T (rs2075685), C-571T (rs2075686), intron 3 DIP (rs28360071), S247A (rs3734091) and intron 7 DIP (rs28360317) with colorectal cancer risk in a Taiwanese population was investigated. The genotypes of XRCC4 of 370 patients with colorectal cancer and 370 age- and gender-matched healthy controls were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. We found significant differences in the genetic and allelic frequencies of the XRCC4 G-1394T between the colorectal cancer and control groups (p=0.0003 and 8.32 x 10(-5), respectively). The distributions of other genetic polymorphisms between cases and the control group were not significantly different. We conclude that the G allele of XRCC4 G-1394T may contribute to colorectal carcinogenesis and may be useful for early detection of colorectal cancer.