Objective To evaluate the feasibility and efficacy of endoscopic resection of gastric sub- mucosal tumors （SMTs） originated from the muscularis propria layer with double peroral endoscopes. Methods In this study two patients with gastric SMTs by auxiliary examination were enrolled. Endoscopic resection was performed using double peroral endoscopes under general anesthesia. The main endoscope was used to resect the tumor and to close the incision of muscularis propria layer by metal clips, while the ancillary endoscope was used to pull and lift tumors or muscularis propria layer. Treatment effectiveness was observed. Results The two gastric SMTs originated from the muscularis propria layer were removed integrally, and were diagnosed pathologically as gastrointestinal stromal tumor and leiomyoma, respectively. The diameter of the lesions was 2 cm. The procedure time were 48 min and 66 min. No complication including perforation or bleeding was observed. The hospitalization time were 8 d and 6 d. Conclusion Endoscopic resection by double peroral endoscopes,is an efficacious and safe endoscopic procedure to resect gastric SMTs originated from the muscularis propria layer, and is able to achieve the efficacy equivalent to surgery.