BACKGROUND: Post-colonoscopy colorectal cancer (PCCRC) represents a potential missed opportunity to diagnose or prevent colorectal cancer (CRC). This study aimed to create a standardized, nationwide audit system to determine why PCCRCs occur and to generate evidence to aid prevention. METHODS: PCCRCs occurring 6-48 months after colonoscopy were identified from English national datasets and uploaded to a secure portal. The portal contained case review forms based on World Endoscopy Organization (WEO) recommendations for PCCRC review. National Health Service colonoscopy providers (n = 126) were asked to review ≤ 25 PCCRCs. The data were analyzed to determine the characteristics of and reasons for PCCRC. RESULTS: Of 2859 PCCRCs, 1724 (60.3 %) were reviewed. Colonoscopies were mostly performed for symptoms (59.2 %) or surveillance (26.5 %). PCCRCs were more common at the hepatic and splenic flexures and transverse colon compared with detected CRCs. PCCRC WEO categorizations were: possible missed lesion, examination adequate 68 %; possible missed lesion, examination inadequate 18 %; detected lesion, not resected 9 %; and likely incompletely resected lesion 5 %. Overall, 69.0 % of PCCRCs were avoidable and 44.2 % led to harm, including premature death in 8.0 %. Non-procedural reasons contributed to 27.1 % of PCCRCs: patient factors 10.2 %; clinical decision making 9.5 %; and administrative factors 7.4 %. CONCLUSIONS: This is the largest detailed PCCRC review to date. The majority of PCCRCs were avoidable and caused significant harm. This study clarifies the causes of diagnostic delays and highlights high-risk patients and areas of the colon, and suggests what needs to be done to reduce PCCRC in the future.