ObjectivesThe cost‐effectiveness of endoscopic submucosal dissection (ESD) and piecemeal endoscopic mucosal resection (pEMR) for colorectal laterally spreading tumors (LSTs) remains unclear. We examined the cost‐effectiveness of these procedures for cases of colon/rectal LST‐non‐granular‐type ≥2 cm and LST‐granular‐mixed‐type ≥3 cm.MethodsWe performed a simulation model analysis using parameters based on clinical data from the National Cancer Center Hospital, Tokyo, and previous literature. The number of recurrences and surgeries and the required costs for 5 years following ESD and pEMR were assessed. Japanese cost data were used in the base‐case analysis, and probabilistic sensitivity analysis (PSA) was performed. The Swedish cost data were used in the scenario analysis.ResultsEndoscopic submucosal dissection yielded a considerably lower number of recurrences and surgeries but required a higher cost than pEMR. The recurrence rates following ESD and pEMR were 0.9–1.3% and 21.1–25.9%, respectively. The incremental cost‐effectiveness ratios for an avoided recurrence and surgery for ESD against pEMR were 376,796–476,496 JPY (3575–4521 USD) and 7,335,436–8,187,476 JPY (69,604–77,689 USD), respectively. PSA demonstrated that the probability of ESD being chosen as a more cost‐effective option than pEMR was >50% at willingness‐to‐pay values of ≥400,000–500,000 JPY (3795–4744 USD) for avoiding a recurrence and ≥9,500,000–10,500,000 JPY (90,143–99,631 USD) for avoiding a surgery. In the scenario analysis, the required cost was also lower for ESD.ConclusionsOur findings suggest potentially favorable cost‐effectiveness of ESD, depending on cost settings and the willingness‐to‐pay value for avoiding recurrence/surgery.