PURPOSE: The provision of comfortable and safe environment for painless gastroscopy in obese patients is an urgent clinical problem. This study aimed to determine the efficacy and safety of the novel Li anesthetic protocol for obesity (LAPO) which included remifentanil-propofol regimen, manual right hypochondrial compression (MRHC), easy-to-create mask, and jaw thrust at preoperative painless gastroscopy in obese patients. PATIENTS AND METHODS: This prospective, single-center, single-arm trial recruited 106 participants underwent LAPO for gastroscopy. The primary outcome was the incidence of hypoxemia (peripheral oxygen saturation [SpO RESULTS: The 98 obese patients under LAPO, the median body mass index (BMI) was 39.2 kg/m CONCLUSION: Compared with CAPO, LAPO reduced the incidence of hypoxemia from 40.4% to 27.5%, so, LAPO was safe and effective for painless gastroscopy. The finding might provide some new schedules for anesthetic management in the absence of advanced airway support instruments. CLINICAL TRIAL REGISTRATION: ChiCTR2300077889.