Background Given the high morbidity and mortality rates for surgery and the diminishment of quality of life caused by operative resection of the gastric cardia, a minor invasive treatment without loss of curability is desirable for submucosal tumors (SMTs) of the esophagogastric junction (EGJ). Endoscopic submucosal dissection (ESD) has been used successfully for the removal of esophageal or gastric SMTs; however, the EGJ has been regarded as a difficult location for ESD because of its narrow lumen and sharp angle. Objective To evaluate the clinical impact of ESD for SMTs of the EGJ arising from the muscularis propria layer. Design Single-center, prospective study. Setting Academic medical center. Patients 143 patients with 143 SMTs of the EGJ originating from the muscularis propria layer. Interventions ESD. Main Outcome Measurements Complications, en bloc resection rate, local recurrence, and distant metastases. Results The average maximum diameter of the lesions was 17.6 mm (range 5 - 50 mm). The en bloc resection rate was 94.4% (135/143). All en bloc resection lesions showed both lateral and deep tumor-free margins, including 20 GI stromal tumors. Perforations occurred in 6 patients (4.2%, 6/143), and metal clips were used to occlude the defect. Four pneumoperitoneum and 2 pneumothorax caused by perforations were resolved with nonsurgical treatment. Local recurrence and distant metastasis have not occurred during a 2-year follow-up. Limitations Single-center, short follow-up. Conclusions ESD appears to be a safe, feasible, and effective procedure for providing accurate histopathologic evaluations, as well as curative treatments for SMTs of the EGJ originating from the muscularis propria layer.