Abstract Background Remimazolam recently became available as a sedative. The comparison of the respiratory suppression effects of remimazolam and propofol under deep sedation for colonoscopy was not thoroughly unclear, particularly with regard to the novel metric of time to first airway intervention. The goal of this study was to systemically compare the respiration profiles of the patients sedated with remimazolam and propofol at the comparable sedation level in the patients undergoing colonoscopy. Methods Four hundred-fifty outpatients were randomly assigned to remimazolam (Group Rem, n = 225) and propofol (Group Pro, n = 225). The target sedation level was the modified Observer’s Assessment of Alertness/Sedation ≤ 2. The primary outcome was elapsed time from anesthesia induction to first airway intervention. Secondary outcomes included incidence and severity of hypoxia and apnea, minute ventilation (MV), tidal volume (TV), and respiratory rate (RR). Results The elapsed time from induction to the first airway intervention was 11 ± 8 min in Group Rem (n = 208) vs. 5 ± 6 min in Group Pro (n = 208, P