Genetic variants in the calcium/vitamin D metabolic pathway may be related to risk for colorectal cancer. While several investigations of vitamin D receptor (VDR) polymorphisms and colorectal cancer have been conducted, no studies to date have evaluated the association of genetic variation in the heterodimer partner for VDR, the retinoid X receptor (RXR). Another important gene in this pathway is the calcium-sensing receptor (CASR). Employing a discordant-sibship case-control design, we examined the association between single nucleotide polymorphisms (SNPs) in RXRA and CASR and risk for colorectal cancer overall and by colorectal subsite and microsatellite instability (MSI) status using data from the Colon Cancer Family Registry. No gene-level relationships between RXRA or CASR and colorectal cancer overall were observed. However, for RXRA SNP rs7861779, a high-interest SNP selected for study apriori, there was a statistically significantly increased risk for proximal colorectal cancer among those with at least one A allele [odds ratio (OR)=1.42; 95% confidence interval (CI)=1.03-1.97]. Another selected RXRA SNP, rs12004589, was significantly associated with risk of MSI-high cancers (OR=2.27; 95% CI=1.13-4.56). Additionally, CASR SNP rs1801726 was significantly associated with a reduced risk for rectal cancer (OR=0.53; 95% CI=0.29-0.96). These results provide support that RXRA SNPs rs7861779 and rs12004589 and CASR SNP rs1801726 may be important markers for colorectal neoplasia. Further work is needed to elucidate their role in the carcinogenic pathway.