Endoscopic volume reduction of the stomach may provide a minimally invasive alternative for surgical procedures in the treatment of obesity. To assess safety and preliminary effectiveness in the first human application of a novel endoscopic stapling technique. Prospective, observational, phase 1 study. Two university hospitals in The Netherlands. Patients with a body mass index (BMI) of 40 to 45 kg/m(2) or 30 to 39.9 kg/m(2) with obesity-related comorbidity. Gastric volume reduction with an endoscopic stapler. Primary outcome measure was the prevalence of serious or mild adverse events. Reduction of excess body weight after 12 months was assessed as a secondary outcome measure for effectiveness of the procedure. Seventeen patients with a median BMI of 40.2 kg/m(2) (interquartile range [IQR] 37.6-42.8) underwent an endoscopic stapling procedure. Median procedure time was 123 minutes (IQR 95-129). No serious adverse events occurred. Adverse events were gastric pain (n = 7, range 1-3 days), sore throat (n = 4, 2-3 days), diarrhea (n = 4, 2-15 days), nausea (n = 3, 2-4 days), constipation (n = 4, 3-14 days), and vomiting (n = 3, 1-4 days). All adverse events were mild and resolved with conservative treatment within 15 days after surgery. The median percentage excess weight loss in the first year was 34.9% (IQR 17.8-46.6). Limited number of patients. This first human application of this endoscopic stapler demonstrates that the procedure is technically feasible and safe. One hundred sixty plications were created in 17 patients without significant problems. Weight loss after 1 year is promising, but long-term follow-up and randomized, controlled studies should evaluate whether this procedure is an effective and durable minimally invasive endoscopic treatment for obesity. ( NCT01429194.