Background and Objectives: One of the genes that has been proven to play a role in colorectal cancer is IL1RL1 (Interleukin 1 receptor like 1). This gene encodes a receptor for interleukin 33 that has been shown with its ligand, to be involved in colorectal cancer. Several single nucleotide polymorphisms are involved in regulating the expression of IL1RL1 gene, so that this study investigated the association between genotypes of rs6543115 polymorphism in the promoter of IL1RL1 gene and colon cancer. Materials and Methods: In this descriptive study, genomic DNA was extracted from blood samples of 100 patients with colon cancer and 100 healthy individuals. The region containing the desired polymorphic site was amplified using appropriate primers and PCR technique, and then was sequenced, and all samples were genotyped. Finally, logistic regression analysis and chi-square test were used to assess the association between rs6543115 genotypes in IL1RL1 gene and colon cancer. Results: The results showed that genotype GC (OR= 0. 273, 95%CI: 0. 090-0. 827, p= 0. 022) and CC (OR= 0. 086, 95%CI: 0. 032-0. 232, p<0. 001) as a risk factor in comparison to genotype GG, significantly decreased the susceptibility of colon cancer. Also, the results showed that the allele C, in comparison to allele G, significantly reduced the risk of colon cancer (OR= 0. 119, 95%CI: 0. 066-0. 232, p< 0. 001). Conclusion: The rs6543115 polymorphism in the IL1RL1 gene appears to be associated with the risk of colon cancer.