Background: Cyclooxygenase-2 (COX-2) main product is Prostaglandin E2 (PGE2) which cause mitogenesis and inflammation. COX-2 is the product of prostaglandin-endoperoxide synthase 2 (PTGS2) gene expression. COX-2 dysregulation can cause angiogenesis, differentiation, and promotion of cancer and its suppression related to control of the tumor's size, number, and cell shape. This study focused on the association of COX-2 expression with colorectal carcinoma (CRC) among Iranian patients on mRNA level and in the Cancer Genome Atlas Program (TCGA) colon and rectum RNAseq dataset, and its relation with pathological features. Methods: PTGS2 expression was assayed by quantitative-PCR method from 90 tissue samples collected from 45 participants. The control samples come from the non-tumor area of the same patients. The data analyzed based on ΔΔCq. The PTGS2-RNAseq data extracted and analyzed by UCSC Xena browser, and its association assessed the occurrence of CRC and invasive-features. Results: PTGS2 showed very significant over-expression in tumor tissues (p< 0.0001) with an N-fold expression of 2.25. But, there was not any significant association between PTGS2 and CRC invasivepathological features such as Lymphatic, vascular and perineural invasion, the Grades of cancer, and Pathologic-M in both parts of this study. Conclusions: The increase in PTGS2 is related to the occurrence of CRC among patient samples. But in both part of this study, PTGS2 is not an invasive factor, and it does not affect the cell differentiation of tumors and metastasis. Based on the high N-fold for patient samples, it can be a strong candidate as a CRC initiator biomarker.