Background <p>Hypoxemia occurs in people living with obesity undergoing gastroscopy under intravenous anesthesia. Preventing hypoxia in people living with obesity with appropriate anesthetics is therefore important. This study aims to compare the safety and efficacy of ciprofol versus propofol, both combined with sufentanil, for sedation during gastroscopy in people living with obesity.</p> Methods <p>This prospective, randomized, controlled trial was conducted at the Endoscopic Center of Hangzhou Red Cross Hospital. Between August 2023 and August 2024, 652 patients were assessed for eligibility. Subsequently, Patients aged 18-65 years, classified as American Society of Anesthesiologists II, with a body mass index (BMI) between 30 and 40 kg/m², were enrolled. Participants were randomly assigned to receive either ciprofol or propofol, both combined with sufentanil, during their gastroscopy. The trial was registered with the Chinese Clinical Trial Registry (ChiCTR2300074217).</p> Results <p>The primary outcome, hypoxemia, occurred in 34.3% of propofol patients vs 19.1% with ciprofol (absolute difference 15.2%; 95% CI 4.9--29.9%). For secondary outcomes, the propofol group experienced significantly more apnea episodes (17.9% vs 5.9%; absolute difference 12%; 95% CI 1.3% to 22.8%) and lower minimum SpO₂ values (90 [80 to 95] vs 93 [90 to 97]; absolute difference --3; 95% CI --8 to 1). Endoscopist satisfaction was higher with ciprofol (4 [3 to 5] vs 5 [4 to 5]; absolute difference --1; 95% CI --1 to 0), and injection pain was significantly more frequent in the propofol group (26.9% vs 1.5%; absolute difference 25.4%; 95% CI 14.4% to 36.4%).</p> Conclusions <p>Ciprofol combined with sufentanil for gastroscopy sedation in people living with obesity, results in lower incidences of hypoxemia and injection pain, shorter apnea duration, and higher endoscopist satisfaction compared to propofol.</p> Trial Registration <p>Chinese Clinical Trial Registry: ChiCTR2300074217; 2023/08/01.</p>