To determine the long-term outcomes after colorectal endoscopic submucosal dissection (ESD), we conducted a large, multicenter, prospective cohort trial with a 5-year observation period. Between February 2013 and January 2015, we consecutively enrolled 1740 patients with 1814 colorectal epithelial neoplasms ≥20 mm who underwent ESD. Patients with noncurative resection (non-CR) lesions underwent additional radical surgery, as needed. After the initial treatment, intensive 5-year follow-up with planned multiple colonoscopies was conducted to identify metastatic and/or local recurrences. Primary outcomes were overall survival, disease-specific survival, and intestinal preservation rates. The rates of local recurrence and metachronous invasive cancer were evaluated as the secondary outcomes. The 5-year overall survival, disease-specific survival, and intestinal preservation rates were 93.6%, 99.6%, and 88.6%, respectively. Patients with CR lesions had no metastatic occurrence, and patients with non-CR lesions had 4 metastatic occurrences. Kaplan–Meier curves revealed that overall survival and disease-specific survival rates were significantly higher in patients with CR lesions than in those with non-CR lesions (P > .001 and P = .009, respectively). Local recurrence occurred in only 8 lesions (0.5%), which were successfully resected by subsequent endoscopic treatment. Multiple logistic regression analyses revealed that piecemeal resection (hazard ratio, 8.19; 95% CI, 1.47–45.7; P = .02) and margin-positive resection (hazard ratio, 8.06; 95% CI, 1.76–37.0; P = .007) were significant independent predictors of local recurrence after colorectal ESD. Fifteen metachronous invasive cancers (1.0%) were identified during surveillance colonoscopy, most of which required surgical resection. A favorable long-term prognosis indicates that ESD can be the standard treatment for large colorectal epithelial neoplasms. Clinical Trial Registration Number: UMIN000010136. Display omitted Accurate histologic assessment facilitated by endoscopic submucosal dissection enables stratification of the risk of lymph node metastasis and determines the necessity of additional surgery, which may have led to a good long-term prognosis.