BACKGROUND/AIMS: This study's purpose was to examine the relationship between appropriateness criteria and diagnostic yield of colonoscopy. METHODOLOGY: This observational study prospectively included consecutive patients referred for colonoscopy from 21 centers in 11 countries. Patient, center, and colonoscopy characteristics were collected. Significant diagnoses included cancer, adenomatous polyps, angiodysplasia, and new diagnoses of inflammatory bowel disease. Appropriateness criteria were developed by the European Panel on the Appropriateness of Gastrointestinal Endoscopy (EPAGE) using the RAND Appropriateness Method. Determinants associated with a significant diagnosis were examined using multiple logistic regression. RESULTS: 5,213 patients who underwent diagnostic colonoscopy were included in the study. There were 1,227 (24%) significant diagnoses made, including 218 (4%) cancers and 735 (14%) adenomatous polyps. Among patients who had a significant diagnosis, 53% had an appropriate indication, 25% had an uncertain indication and 22% had an inappropriate indication. Having an appropriate indication, increasing age, and male sex increased the odds of finding a significant diagnosis at colonoscopy. CONCLUSIONS: Appropriateness criteria enhanced the detection of significant lesions, thereby demonstrating one way to enhance quality of care. However, appropriateness criteria will never perform better than the imperfect relationship between clinical symptoms and diagnostic yield.