ABSTRACT Gastroparesis is defined as a gastrointestinal motility disorder with objectively delayed gastric emptying of solids in the absence of mechanical obstruction, associated with upper gastrointestinal symptoms including early satiety, postprandial fullness, nausea, vomiting, bloating, and upper abdominal pain. The pathophysiology of gastroparesis includes postprandial antral hypomotility and pylorospasm, which may reflect extrinsic (vagal) denervation, enteric (intrinsic) neuropathy involving excitatory or inhibitory neurons or electrical syncytium (such as interstitial cells of Cajal) which may result from imbalance of CD206-positive macrophages that protect these intrinsic mechanisms. The introduction of G-POEM involving endoscopic pyloromyotomy has focused attention on pyloric dysfunction as a potentially important factor in the pathogenesis of this syndrome. However, many unknowns remain. First, the reported trials are uncontrolled with results that are short-term and inconsistent so the true efficacy of this procedure is not clear. Second, given that it is unlikely that G-POEM is a panacea for all patients, it is important to determine which of several possible factors influence outcome e.g. etiology (specifically diabetic versus idiopathic gastroparesis); demographic factors (age, BMI, psychological factors, duration of illness), baseline severity of gastric retention; gastric dysrhythmia, pyloric distensibility or scarring (as measured by EndoFLIP), postprandial antral motility and “isolated” pylorospasm (tonic elevation of baseline pressure independent of antral contractions). Our general hypothesis is that G-POEM is efficacious in relieving some or all symptoms of gastroparesis and that efficacy differs according to diagnosis, baseline retardation of gastric emptying, antropyloroduodenal motility and pyloric sphincter diameter and compliance. We will examine this hypothesis in a controlled short- term study that will inform future, more definitive trials on G-POEM on the optimal patient selection and outcome criteria. The aims of this pilot and feasibility, hypothesis-generating study are: Aim 1: To evaluate the 12-month treatment effect of peroral endoscopic pyloromyotomy (G-POEM) vs. sham surgery in patients with drug-refractory gastroparesis, as measured by validated questionnaires and to perform a pilot analysis of factors predictive of the outcome including demographics, etiology, vagal dysfunction, in vivo gastric physiology, (emptying of solids, postprandial antral motility, gastric dysrhythmia and pyloric motor functions). Aim 2. To compare the long-term (1 year or more) outcomes in patients randomized to G-POEM with matched patients prospectively followed in the national Gastroparesis registry run by the Gastroparesis Clinical Research Consortium (GpCRC). .