Low selenium (Se) status correlates with increased risk of colorectal cancer (CRC). Since Se exerts its biological roles through the selenoproteins, genetic variations in selenoprotein genes may influence susceptibility to CRC. This study analysed 12 single-nucleotide polymorphisms (SNPs) in selenoprotein genes [glutathione peroxidase 1 (GPX1), GPX4, 15 kDa selenoprotein (SEP15), selenoprotein S (SELS), selenoprotein P (SEPP1) and thioredoxin reductase 2 (TXNRD2)] and in genes that code for a key protein in Se incorporation [SECIS-binding protein 2 (SBP2)] and in antioxidant defence [superoxide dismutase 2 (SOD2)] in relation to sporadic CRC incidence. CRC patients (832) and controls (705) from the Czech Republic were genotyped using allele specific PCR. Logistic regression analysis showed that three SNPs were significantly associated with an altered risk of CRC: rs7579 (SEPP1), rs713041 (GPX4) and rs34713741 (SELS). The association of these SNPs with disease risk remained after data stratification for diagnosis and adjustments for lifestyle factors and sex. Significant two-loci interactions were observed between rs4880 (SOD2), rs713041 (GPX4) and rs960531 (TXNRD2) and between SEPP1 and either SEP15 or GPX4. The results indicate that SNPs in SEPP1, GPX4 and SELS influence risk of CRC. We hypothesize that the two-loci interactions reflect functional interactions between the gene products. We propose that these variants play a role in cancer development and represent potential biomarkers of CRC risk.