BACKGROUND: Gastrointestinal endoscopy with sedation is frequently complicated by hypoxemia. Nasal cannulas have limitations in eliminating hypoxemia. We hypothesized that the combination of nasal clips and nasal cannulas would improve the inspired oxygen concentrations and prevent hypoxemia compared with the use of nasal cannulas alone. METHODS: A total of 600 adult patients were randomly assigned to receive supplemental oxygen through single-lumen nasal cannulas or through the combination of nasal clips and nasal cannulas. The primary outcome was the incidence of hypoxemia. Additionally, subclinical respiratory depression and severe hypoxemia, duration of hypoxemia, lowest SpO RESULTS: Three hundred patients in the nasal clip group and 296 patients in the nasal cannula group were included in the intention-to-treat analysis. Nasal clips significantly decreased the incidence of hypoxemia from 25.0-17.7%(RR = 0.707, 95% CI = 0.516 to 0.967, P = 0.029). The median and interquartile range of lowest SpO CONCLUSIONS: The combination of nasal clips and cannulas reduces hypoxemia during gastrointestinal endoscopy with sedation, demonstrating a significant advantage over the sole use of nasal cannulas, with tolerable adverse events. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR2200065407).