BACKGROUND & AIMS:Post-colonoscopy colorectal cancers (PCCRCs) may arise from missed lesions or due to molecular features of tumors that allow them to grow rapidly. We aimed to compare clinical, pathology, and molecular features of PCCRCs (those detected within 6-60 months of colonoscopy) and detected CRCs (those detected within 6 months of a colonoscopy). METHODS:Within a population-based cross-sectional study of incident CRC cases in Utah (from 1995 through 2009), we identified PCCRCs (those cancers that developed within 5 years of a colonoscopy) and matched the patients by age, sex, and hospital site to patients with detected CRC.Archived specimens were retrieved and tested for microsatellite instability (MSI), CpG island methylation, and mutations in KRAS and BRAF. There were 2659 cases of CRC diagnosed within the study window; 6% of these (n [ 159) were defined as PCCRCs; 84 of these cases had tissue available and were matched to 84 subjects with detected CRC. RESULTS:Higher proportions of PCCRCs than detected CRCs formed in the proximal colon (64% vs 44%; P [ .016) and were of an early stage (86% vs 69%; P [ .040). MSI was observed in 32% of PCCRCs compared with 13% of detected CRCs (P [ .005). The other molecular features were found in similar proportions of PCCRCs and detected CRCs. In a multivariable logistic regression, MSI (odds ratio, 4.20; 95% CI, 1.58-11.14) was associated with PCCRC. There was no difference in 5-year survival between patients with PCCRCs vs detected CRCs. CONCLUSION:In this population-based cross-sectional study of incident CRC cases in Utah, we found PCCRCs to be more likely to arise in the proximal colon and demonstrate MSI, so PCCRCs and detected CRC appear to have different features or processes of tumorigenesis. Additional studies are needed to determine if post-colonoscopy cancers arise through a specific genetic pathway. P ost-colonoscopy colorectal cancers (PCCRCs) are a small but clinically important subset of colorectal cancers (CRCs) that refer to cancers that are diagnosed after a colonoscopy in which no cancer is diagnosed. 1 The reported prevalence of PCCRC in various population-based studies across the world range from 3% to 9%, with an estimated pool prevalence of 3.7%. 2 The pathogenesis of PCCRC is likely multifactorial, including cancers and precursor adenomas that are missed or incompletely excised at colonoscopy or unique molecular pathways. Several patient factors (female gender, diverticulosis) and endoscopist factors (non-gastroenterologist physician, rural facility, low adenoma detection rate) have emerged as risk factors for PCCRC. 2-5 However, certain tumor characteristics Abbreviations used in this paper: