Based on our experience with endoscopic submucosal dissection (ESD) and new endoscopic techniques for endoscopic closure of iatrogenic upper gastrointestinal (upper-GI) perforations, we developed methods to remove upper-GI subepithelial tumors (SETs) originating from the muscularis propria by endoscopic muscularis dissection (EMD). The aim of this study is to evaluate the clinical feasibility and safety of EMD. 31 patients with upper-GI SETs originating from the muscularis propria were treated by EMD. The EMD differed from ESD in (1) precutting the overlying mucosa above the lesion by using snare or longitudinal incision instead of circumferential incision, (2) dissecting the complete tumors away from submucosal and muscularis propria tissue by electrical dissection combined with blunt dissection, and (3) closing the wound with clips. Perforations occurring during dissection were closed by endoscopic methods. 30 of 31 tumors were resected completely (96.8 %). One esophageal lesion was resected partially because of severe adhesions with surrounding tissue. Mean resected tumor size was 22.1 mm x 15.5 mm, and mean operation time was 76.8 min (range 15-330 min). Histological diagnosis was gastrointestinal stromal tumor (GIST) in 16 lesions [6 esophageal, 3 cardial, 7 gastric; 6 very low risk and 10 low risk according to the National Institutes of Health (NIH) risk classification] and leiomyoma in 15 lesions (8 esophageal, 4 cardial, 3 gastric). No patient developed delayed hemorrhage. Perforation occurred in four patients (12.9 %), all of which were managed successfully by endoscopic techniques. The mean follow-up time was 17.7 months (range 7-35 months). Follow-up found no tumor recurrence in any patient. In this early experience, EMD appears to be a feasible and minimally invasive treatment for some patients with upper-GI SETs originating from the muscularis propria. Although there is a higher risk of perforation than with ESD, this will improve with extended practice, and perforations have become manageable endoscopically.