Abstract Studies suggest that polymorphisms of the vitamin D receptor (VDR) gene may influence colorectal cancer risk. In this study, we examine the association of the CDX2 VDR polymorphism (rs11568820) located in the 5′-untranslated region of the gene, and VDR haplotypes, including this polymorphism, with colon and rectal cancer using data from two large case-control studies of colon (N = 1,574 cases and 1,970 controls) and rectal (n = 791 cases and 999 controls) cancer. The frequency of the A allele of the CDX2 polymorphism was 19% among non–Hispanic white, 21% among Hispanic, 76% among African American, and 47% among Asian controls. The CDX2 polymorphism was not independently associated with either colon or rectal cancer, nor did it modify associations of dietary calcium, vitamin D, or fat with colon or rectal cancer. However, the bLFA haplotype which occurred in 6.5% of non–Hispanic white participants and 41.2% of African American participants was associated with an increased risk of colon cancer, and an odds ratio of 2.4 [95% confidence intervals (CI), 2.45 (1.38-4.38)]. The BSfG haplotype was associated with a 1.61 (95% CI, 1.05-2.49) increased risk of rectal but not colon cancer, whereas the BSFA haplotype was associated with a significantly reduced risk of rectal (odds ratio, 0.71; 95% CI, 0.52-0.97) but not colon cancer. These data suggest that haplotype analysis that encompasses different domains of the VDR gene might further our understanding of associations between the VDR gene and colon and rectal cancer. (Cancer Epidemiol Biomarkers Prev 2007;16(12):2752–5)