Background: Intestinal cancer the third most prevalent malignancy and leading cause of cancer mortality worldwide, is colorectal cancer (CRC). More than one-third of colorectal cancer cases in Egypt include people under the age of 40 who are found to have the disease at an advanced stage. Due to its function in human tumours, cyclooxygenase (COX), a crucial enzyme in the prostanoid biosynthesis pathway, has drawn a lot of interest. COX-2 regulates cell proliferation, cell transformation, tumour growth, metastasis, and invasion, and so plays an important role in the origin and development of metaplastic and dysplastic tissues, as well as the beginning and progression of cancer. Increased COX-2 expression has been linked to a variety of epithelial-based premalignant and malignant lesions in the gastrointestinal system, including the colorectal area. Objectives: To investigate the probable link between COX-2 gene polymorphism and colorectal cancer risk. Methods: This is a case-control study with 100 participants. Were selected 50 with colorectal cancer (case group) from Inpatient and Outpatient Oncology Clinic, Faculty of Medicine, Menoufia University and 50 participants without colorectal neoplasia (control group) matched in age and gender with case group. With the use of the usual literature approach, the polymorphism -765G/C COX2 gene was being identified using molecular genetic analysis. Clinical and pathological data from the patient were also examined. The findings demonstrated a link between the existence of the COX2 gene polymorphism and susceptibility to colorectal cancer in this pattern, with a significant incidence of GC and CC genotype in those with colorectal cancer. Additionally, there were variations in allele frequencies between the groups. There was a greater incidence of polymorphism in the left colon when cancer patients were divided based on the location of their tumours. Results: The comparison between the two studied groups indicated the genotype distribution of COX 2 gene polymorphisms in CRC patients that was 42%, 50%, and 8% with GG, GC, and CC respectively whereas in control group, it was 76% with GG, 22% with GC, and 2% with CC .The genotypic distribution revealed statistical difference (p=0.003). The allelic frequencies were 67% who had the wild allele G and the remaining 33% had the variant allele C in CRC group while in control group there were 87% with G and 13% with C allele. The difference was statistically significant (p=0.001). The GC genotype revealed a significant risk of CRC as compared to GG genotype. Subjects carrying the C allele had a significant risk of CRC compared to those carrying the allele G Conclusion: The COX2 gene polymorphism is linked to an increased risk of colorectal cancer, particularly rectosigmoid tumours.