Gastroparesis is a condition characterized by delayed gastric emptying, and a constellation of symptoms, including nausea, vomiting, early satiety, and bloating. Although current surgical options such as pyloroplasty have been shown to be effective, an endoscopic submucosal myotomy technique may be applied to divide the pyloric sphincter without surgical access. Such endoscopic technique may provide the benefits of a natural orifice procedure, and improve gastric emptying in gastroparetic patients. Per-oral pyloromyotomy (POP) was performed in seven female patients aged 33-65 years (mean 51 years). All patients had a pre-operative work-up that included upper endoscopy, and a gastric emptying study. A pH study, and esophageal manometry were also performed when a concomitant fundoplication was considered. POP was technically successful in all seven cases. There were no immediate procedural complications. Perioperative, complications included: one patient with an upper GI bleed 2 weeks post-procedure, necessitating transfusions, and endoscopic clipping of a pyloric channel ulcer; one patient who experienced difficulty swallowing post operatively, delaying discharge by 1 day; and one patient who developed a hospital-acquired pneumonia, delaying discharge by several days. Six of the seven patients experienced significant symptomatic improvement following the procedure. Three month follow-up nuclear medicine solid-phase gastric emptying studies are currently available for 5 of the 7 patients. Normal gastric emptying at 4 h was noted in four of five patients (80 %). One patient did not respond to endoscopic management subsequently underwent an uneventful laparoscopic pyloroplasty, which also failed to significantly improve her symptoms. POP is a technically safe and feasible endoscopic procedure. Early follow-up suggests promising symptomatic improvement as well as objective improvement in gastric emptying. Additional clinical experience is required to establish the role of this technique in the management of gastroparesis.