BACKGROUND: We assessed the feasibility and safety of a fully endoscopic one-anastomosis gastric bypass (OAGB) procedure in obese adult minipigs, with short bypass limb length if feasible or full length in a sham-controlled study. METHODS: A natural orifice transluminal endoscopic surgery (NOTES) OAGB procedure was performed in 4 obese adult Yucatan minipigs. Weight change was compared to 2 sham-controlled animals. Endoscopic examination and necropsy were performed at 15 weeks. RESULTS: A 50-cm bypass limb was unfeasible in the pigs, so the 4 test animals received 150-cm bypasses. By week 15, mean weight gain compared to baseline body weight was 3.6% in 3 surviving test animals and 10.5% in the 2 sham-controlled animals. Two asymptomatic gastrojejunal lumen-apposing metal stents and one asymptomatic duodenal exclusion device migration occurred during follow-up. One pig died on day 60 with intestinal volvulus finding on necropsy. In the surviving test pigs, bypass limb lengths were 360 cm, 120 cm, and 80 cm at necropsy. CONCLUSIONS: In an experimental endoscopic OAGB procedure, a short bypass limb length was unfeasible in adult obese minipigs. Weight gain tended to be reduced in test animals with longer bypass limbs compared to sham-controlled animals. Additional safety testing is needed during the continued development of the procedure.