Background: Natural orifice transluminal endoscopy surgery (NOTES) gastrojejunal anastomosis (GJA) with duodenal exclusion (DE) could be used as a less invasive alternative to surgical gastric bypass. The aim of this study was to compare the efficacy and safety of both methods for bariatric purpose., Methods: This was a prospective, experimental and comparative study on 27 obese living pigs, comparing 4 groups: GJA alone (group 1, G1), GJA + DE (group 2, G2), surgical gastric bypass (group 3, G3), control group (group 4, G4). GJA was endoscopically performed, using NOTES technic and LAMS, while DE was performed surgically for limb length selection. Animals were followed for 3 months. Primary outcome included technical success and weight change, while secondary endpoints included the rate of perioperative mortality and morbidity, histological anastomosis analysis and biological analysis., Results: Technical success was 100% in each intervention group. No death related to endoscopic procedures occurred in the endoscopic groups, while early mortality (< 1 month) was 57,1% in the surgical group, all due to anastomotic dehiscence. At 3 months, compared to baseline, mean weight change was + 3,1% in G1 (p = 0,46); -14,9% in G2 (p = 0,17); +5,6% in G3 (p = 0,38) and + 25% in G4 (p = 0,029). Histopathological analysis of endoscopic GJA showed complete fusion of different layers without leak or abscess., Conclusions: Endoscopic GJA with DE provides the efficacy of bypass on weight control in an animal model. Next steps consist of the development of devices to perform exclusively endoscopically limb length selection and DE., (© 2023. The Author(s).)