BACKGROUND The electrosurgical knives required to perform endoscopic submucosal dissection (ESD) have recently passed the 510(k) premarketing evaluation by the U.S. Food and Drug Administration and are now available for purchase in the United States. Challenges to ESD being more widely performed in the United States include the lack of intensive hands-on training programs and a low incidence of appropriate, highly dysplastic gastric lesions on which an ESD-trained endoscopist can begin performing this procedure in patients. Furthermore, there are no guidelines regarding the safety of continuing antiplatelet therapy in patients undergoing ESD. OBJECTIVE To report on the first gastric ESD performed in the United States by using recently approved electrosurgical knives on a patient who was maintained on aspirin therapy. DESIGN Case report. SETTING Large academic medical center. PATIENT One patient with a 2-cm high-grade dysplasia (HGD) lesion in the posterior antrum who had indwelling coronary stents and was maintained on aspirin therapy throughout the periprocedural period. INTERVENTIONS High-definition white-light and narrow-band imaging endoscopy, endosonography, and ESD by using recently approved electrosurgical knives. MAIN OUTCOME MEASUREMENTS Complete resection of the HGD gastric lesion. RESULTS En bloc complete resection of the HGD gastric lesion was achieved without any immediate or delayed bleeding or perforation. No residual or recurrent dysplasia was found on 1- or 3-month follow-up endoscopies. LIMITATIONS Generalizations cannot be made from this single case. CONCLUSIONS After receiving intensive hands-on training in both ex vivo and in vivo animal models, gastric ESD was successfully performed by 2 U.S. endoscopists by using recently approved electrosurgical knives in a patient maintained on aspirin therapy without any complications.