Background & aims: The term post-colonoscopy colorectal cancer (PCCRC) refers to colorectal cancer (CRC) diagnosed after a negative colonoscopy. Using the root-cause algorithm proposed by the World Endoscopy Organization (WEO), we aimed to investigate plausible explanations for PCCRCs and potential changes in plausible explanations for PCCRCs over time in a Danish Region. Methods: During 1995-2021, we used national health registries and electronic medical records in the Central Denmark Region to identify PCCRC cases, defined as CRCs recorded within 6-48 months after a colonoscopy. We then applied the WEO algorithm to categorize explanations for PCCRC as follows: A) possible missed lesion, prior examination adequate; B) possible missed lesion, prior examination inadequate; C) detected lesion, not resected; or D) likely incomplete resection of previously identified lesion. PCCRCs were identified before (1995-2013) and after (2014-2021) implementation of nationwide FIT-based CRC screening and quality indicators for colonoscopy. Results: We identified 762 PCCRCs, 53.5% among males and 57% among individuals ≥ 70 years. Forty-five percent were located in the proximal colon. We identified 616 (80.8% (95% confidence interval [CI]: 74.6%-87.5%)) category A PCCRCs; 36 (4.7% [95% CI: 3.3-6.5]) category B PCCRCs; 26 (3.4% [95% CI: 2.2-4.9] category C PCCRCs; and 84 (11% [95% CI: 8.8-13.6]) category D PCCRCs. Similar patterns were observed during the early (1995-2013) and late (2014-2021) study periods. Conclusions: Most PCCRCs originate from possible missed lesions and incompletely resected lesions during the complete study period. These findings indicate the importance of quality assurance of colonoscopy procedures and polypectomy techniques.