Objective The standard treatment for submucosal esophageal cancer is esophagectomy or chemoradiotherapy (CRT). However, these treatment modalities could deteriorate the general condition and quality of life of the patients who are intolerant to invasive therapy. It is therefore important and beneficial to develop less invasive treatment protocols for these patients. Methods The study included 43 patients who were clinically suspected of mucosa or submucosal esophageal cancer but underwent endoscopic submucosal dissection (ESD) as a primary treatment, due to the patients' poor performance statuses and/or preferences for less invasive therapy. According to the pathological findings and patient's general condition, whether the patient underwent additional treatments or remained hospitalized without additional treatments was thereafter decided for each patient. We retrospectively analyzed the outcomes of these patients. Results Fifteen patients underwent additional surgery, 11 patients underwent CRT/radiation therapy (RT) and 17 patients were followed without additional treatments. During the 3-year follow-up period, the relapsefree survival rates in the patients who received or did not receive additional treatments were 88% and 64%, respectively (95% confidence interval, 0.45-0.76, p=0.04). The relapse-free and overall survival rates in the patients with additional treatments were equivalent or superior to those described in previous reports of the standard treatments. Preceding ESD contributed to reduce the local relapse significantly to approximately 3.5% and additional CRT-related toxicities. Conclusion Preceding ESD is very effective for the local control of cancer, and useful for histologically confirming the high-risk factors of relapse, such as ! submucosal layer 2 (SM2) invasion and lymphovascular involvements. ESD with additional therapy may be a promising strategy for optimizing the selection of therapy depending on the patient's general condition.