Science Colorectal cancer (CRC) is the third-most-prevalent form of cancer in the world and is commonly found in both sexes. 1 Epigenetic and genetic susceptibility are related to the development of colorectal cancer. 2 Different genetic pathways, such as chromosomal instability (CIN), microsatellite instability (MSI), and CpG island methylator phenotype (CIMP) are involved in the development of the disease. 3 and inflammation is an important risk factor. 4 Several studies 5-7 report that prostaglandins are mediators of carcinogenesis, as well as having influence in hyperproliferation, transformation, tumor growth, invasion, metastasis, angiogenesis, and inhibition of apoptosis. Cyclooxygenase (COX), also known as prostaglandin endoperoxidase H synthase, is a pro-inflammatory enzyme that intercedes in the formation of eicosanoids, such as prostaglandins (PGs) and thromboxans from arachidonic acid (AA). 8 The main cyclooxygenase isoforms are COX-1 and COX-2 (also known as prostaglandin-endoperoxide synthase 1 and 2 [PTGS1 and PTGS2]). 9 COX-1 is constitutively expressed in most tissues, whereas COX-2 is an inducible enzyme that is upregulated by inflammatory cytokines, growth factors, and tumor promoters. 10 Cox-2, mapped to chromosome 1q25.2-q25.3, is 8.3 kb in size. It contains 10 exons and possesses 5' and 3' untranslated regions (UTRs). 11 Polymorphisms in the COX-2 gene (GenBank accession no. AY382629) have been associated with increased risk of different tumors, including colorectal, breast, biliary tract, pancreatic, prostate, lung, esophageal, gastric cancer, and head and neck cancers. ABSTRACT Colorectal cancer is the third-most-prevalent form of cancer in the world. Several studies report that prostaglandins are mediators of carcinogenesis. Cyclooxygenase, also known as prostaglandin endoperoxidase H synthase, is a pro-inflammatory enzyme that intercedes in the formation of eicosanoids from arachidonic acid. Polymorphisms in the COX-2 gene have been associated with increased risk of different tumors, including colorectal. Genetic variations in COX-2 may affect enzyme activity or expression, thereby altering the production of prostaglandins and potentially modulating an individual's inflammatory response and risk of colorectal cancer. A functional polymorphism in the COX-2 promoter region (–765G>C), located at a putative stimulatory protein-1 (SP1) binding site, suggests the involvement of a complex array of factors regulating its expression. This study was designed to evaluate the status of –765G>C poly-morphism (rs20417) and risk of sporadic colorectal cancer in an Iranian population.