Background: Following colorectal polypectomy, 20-50% develop metachronous polyps, and some have increased colorectal cancer (CRC) risk. Surveillance colonoscopy is recommended to high-risk patients, based on index polyp number, histology and size. We aimed to assess if COX2, p53 and beta-catenin expression could predict metachronous polyp/ CRC risk. Methods: Tissue microarrays (TMA’s) were constructed for 339 patients from the INCISE study, a retrospective analysis of all patients undergoing screening polypectomy (Apr’09-Dec’16) followed by surveillance (6months-6years) in Glasgow, UK. Epithelial COX2, p53 and beta-catenin expression were assessed for each patient’s most advanced index polyp using immunohistochemistry, quantified by QuPath software. Kaplan-Meier analysis, log-rank tests and univariate/ multivariate cox regression assessed the association between marker expression and time to metachronous polyp/ CRC detection. Results: Low nuclear p53 expression was associated with shorter time to metachronous polyp/ CRC detection (p=0.024). Low nuclear (p=0.012) and membranous (p=0.046) beta-catenin expression was associated with shorter time to metachronous polyp/ CRC detection. There was no association between cytoplasmic COX2 expression and time to metachronous polyp/ CRC detection overall (p=0.309), but high cytoplasmic COX2 expression was associated with shorter time to detection of advanced metachronous lesions (advanced colorectal polyps/ CRC) (p=0.011). A combined score using the two most powerful biomarkers (nuclear p53 and nuclear beta-catenin – both high/ one low/ both low) was also associated with shorter time to metachronous polyp/ CRC detection (p=0.011). Univariate and multivariate cox regression are shown. Conclusions: Index polyp number and combined nuclear p53/beta-catenin expression independently predicted time to metachronous polyp/ CRC detection.