This study was designed to evaluate the clinical efficacy, safety, and feasibility of endoscopic full-thickness resection (EFR) for gastric submucosal tumors (SMTs) originated from the muscularis propria. Twenty-six patients with gastric SMTs originated from the muscularis propria were treated by EFR between July 2007 and January 2009. EFR technique consists of five major procedures: (1) injecting normal saline into the submucosa and precutting the mucosal and submucosal layer around the lesion; (2) a circumferential incision as deep as muscularis propria around the lesion by the endoscopic submucosal dissection (ESD) technique; (3) incision into serosal layer around the lesion with Hook knife; (4) completion of full-thickness incision to the tumor including the serosal layer with Hook, IT, or snare by gastroscopy without laparoscopic assistance; (5) closure of the gastric-wall defect with metallic clips. EFR was successfully performed in all 26 patients without laparoscopic assistance. The complete resection rate was 100%, and the mean operation time was 105 (range, 60-145) min. The mean resected lesion size was 2.8 (range, 1.2-4.5) cm. Pathological diagnosis of these lesions included gastrointestinal stromal tumors (GISTs) (16/26), leiomyomas (6/26), glomus tumors (3/26), and Schwannoma (1/26). No gastric bleeding, peritonitis sign, or abdominal abscess occurred after EFR. No lesion residual or recurrence was found during the follow-up period (mean, 8 months; range, 6-24 months). EFR seems to be an efficacious, safe, and minimally invasive treatment for patients with gastric SMT, which makes it possible to resect deep gastric lesion and provide precise pathological diagnosis of it. With the development of EFR, the indication of endoscopic resection may be expanded.