Cyclo-oxygenase-2(Cox-2), a key regulator of inflammation-producing prostaglandins, promotes cellproliferation and growth. Therefore, a better understanding of the regulatory mechanisms of Cox-2 could leadto novel targeted cancer therapies. MicroRNAs are strongly implicated in colorectal cancer but their specificroles and functions have yet to be fully elucidated. MiR-1297 plays an important role in lung adenocarcinomaand laryngeal squamous cell carcinoma, but its significance in colorectal cancer (CRC) has yet to be reported.In our present study, we found miR-1297 to be down regulated in both CRC-derived cell lines and clinical CRCsamples, when compared with normal tissues. Furthermore, miR-1297 could inhibit human colorectal cancerLOVO and HCT116 cell proliferation, migration, and invasion in vitro and tumorigenesis in vivo by targetingCox-2. Moreover, miR-1297 directly binds to the 3`-UTR of Cox-2, and the expression level was drasticallydecreased in LOVO and HCT116 cells following overexpression of miR-1297. Additionally, Cox-2 expressionlevels are inversely correlated with miR-1297 expression in human colorectal cancer xenograft tissues. Theseresults imply that miR-1297 has the potential to provide a new approach to colorectal cancer therapy by directlyinhibiting Cox-2 expression.