Background: EMR of advanced mucosal neoplasia (AMN) (ie, sessile or laterally spreading lesions of R20 mm) of the colon has become an increasingly popular alternative to surgical resection. However, data regarding safety and mortality of EMR in comparison to surgery are limited. Objective: To compare actual endoscopic with predicted surgical mortality. Design: Prospective, observational, multicenter cohort study. Setting: Academic, high-volume, tertiary-care referral center. Patients: Consecutive patients referred for EMR. Intervention: EMR. Main Outcome Measurements: To predict hypothetical surgical mortality, the Association of Coloproctology of Great Britain and Ireland score, composed of physiological and surgical components, was calculated for each patient. Predicted surgical mortality was then compared with actual outcomes of EMR. The results were validated by an unselected subcohort by using the Colorectal Physiologic and Operative Severity Score for Enumeration of Mortality and Morbidity. Results: Among 1050 patients with AMN treated by EMR, including patients with a predicted mortality rate of greater than 5% (13.8% of cohort), no deaths occurred within 30 days after the procedure. The predicted surgical mortality rate was 3.3% with the Association of Coloproctology of Great Britain and Ireland score (P<.0001). This suggests a significant advantage of EMR over surgery. The results were validated by using the Colorectal Physiologic and Operative Severity Score for Enumeration of Mortality and Morbidity in 390 patients predicting a surgical mortality rate of 3.2% (P = .0003). Limitations: Nonrandomized study. Conclusion: In this large multicenter study of EMR for colonic AMN, the predicted surgical mortality rate was significantly higher than the actual endoscopic mortality rate. Given that endoscopic therapy is less morbid and less expensive than surgery and can be performed as an outpatient treatment, it should be considered as the first line of treatment for most patients with these lesions.