Colorectal cancer (CRC) is one of the leading cancers worldwide. Through genome wide association studies, several single nucleotide polymorphisms scattered in the genome emerged to be influential in the development of sporadic CRC in some populations. However, replicative studies failed to prove a particular SNP-CRC association in populations and ethnic groups. Cyclooxygenase-2 (PTGS2) is a crucial enzyme involved in the metabolism of prostaglandins. The aim of this replicative study is to investigate the possible association between PTGS2 -765G>C polymorphism and sporadic CRC risk in a subset of Iranian population. A total of 110 patients with sporadic CRC, and 120 controls were genotyped for PTGS2 -765G>C polymorphism by using polymerase chain reaction-based restriction fragment length polymorphism. There were no significant differences in the genotype and allele frequencies of PTGS2 -765G>C between two groups except in irregular aspirin or non-steroidal anti-inflammatory drugs (NSAID) consumers. Frequencies of genotypes and alleles were as follows: GG = 44.2, GC = 48.3, CC = 7.5%, in controls and GG = 34.55, GC = 60.9, CC = 4.55% in cases. Regarding the allele frequency, the following values were found: G = 65, C = 35% in cases and 68.3, 31.7% in the controls, respectively. In irregular aspirin or NSAID consumers combined GC+CC genotype was found to be a risk genotype (OR = 1.933, 95% CI: 1.067-3.501, P = 0.036). Overall, no significant relation was found between this polymorphism and sporadic CRC in Iranians. However, in irregular aspirin or NSAID consumers the combined GC+CC genotype proved to be a risk genotype.