Endoscopic resection for early esophageal cancer has a risk of residual margins. The risk these residual margins pose have not been fully evaluated. The present study aimed to investigate the associated risk factors and prognosis of residual margins following the endoscopic resection of early esophageal squamous cell carcinoma. In total, 369 patients (381 lesions) with early esophageal squamous cell carcinoma treated in the Fourth Hospital of Hebei Medical University (Shijiazhuang, China) with endoscopic resection were retrospectively analyzed. Sex, age, location, tumor diameter, depth of tumor invasion, endoscopic treatment, endoscopic ultrasonography (EUS) before resection, work experience of endoscopists and the degree of tumor differentiation were all evaluated as potential risk factors. In addition, the prognosis of patients with positive margins were analyzed. A total of 73 patients (73/381, 19.2%) had positive margins after endoscopic resection. Amongst the 65 patients who were successfully followed up, five patients succumbed to cardiovascular and cerebrovascular diseases, one patient received radiotherapy, two patients received radiotherapy and chemotherapy whilst one patient received chemotherapy. By contrast, 12 patients received surgery and 20 patients received additional endoscopic mucosal resection or endoscopic submucosal dissection. The other 29 patients were followed up regularly and no recurrence could be found. Univariate analysis revealed that tumor diameter, endoscopic treatment, depth of invasion, EUS before resection, degree of tumor differentiation and direction of invasion were all associated with the positive margin. Multivariate logistic regression analysis then found that EUS before resection, degree of tumor differentiation and depth of tumor invasion are independent risk factors for positive margins after endoscopic resection. These results suggest that poorly differentiated lesions and deeper invasion depth can increase the risk of positive margin after endoscopic resection. As a result, EUS evaluation before resection may reduce the risk of invasion depth. In addition, for poorly differentiated lesions, more aggressive treatment regimens may be recommended for preventing recurrence.Copyright: © Feng et al.