Background <p>Remimazolam is a new alternative drug combining the efficacy and safety advantages of midazolam and propofol. However, studies comparing remimazolam with midazolam in diagnostic upper gastrointestinal endoscopy are insufficient. The purpose of this study was to prove the efficacy and safety of remimazolam in diagnostic upper gastrointestinal endoscopy compared with midazolam.</p> Methods <p>This study is a randomized, controlled, multicenter trial. Participants who are to receive diagnostic upper gastrointestinal endoscopy are enrolled and randomly assigned to the remimazolam or midazolam group (control group) at a 1:1 ratio. Remimazolam is given (with an initial 5&#xa0;mg plus an additional 2.5&#xa0;mg, maximum 5 times) in the remimazolam group for endoscopic sedation and midazolam is given (with an initial 2&#xa0;mg plus an additional 1~2&#xa0;mg, maximum 5 times) in the control group. Flumazenil can be given at the discretion of the investigator. Vital signs, level of consciousness, and adverse events are assessed from the administration of sedatives to the full recovery of consciousness. The primary endpoint is total procedure time, which is defined as the time from the first administration of sedatives to discharge. The secondary endpoints include the success rate of sedation, recovery time, induction time, total endoscopy time, discharge time, sedation time, incidence of hypotension, respiratory depression, tachycardia, bradycardia, participant satisfaction, and paradoxical response incidence.</p> Discussion <p>The results of this trial are expected to prove the superior efficacy of remimazolam with favorable safety. Based on the results, a sedation method using remimazolam would be applied preferentially for diagnostic upper gastrointestinal endoscopy in clinical practice.</p> Trial registration <p>Clinicaltrials.gov NCT05836545. Registered on April 19, 2023</p>