AIM: To observe and compare the clinical efficacy and safety of remimazolam and propofol alone and in combination in endoscopic retrograde cholangiopancreatography (ERCP) anesthesia. METHODS: A total of 120 patients undergoing elective ERCP were divided into the propofol group (P group), the remimazolam group (R group), and the remimazolam combined with propofol group (RP group) according to a random number table, with 40 patients in each group, and the three groups completed anesthesia according to the designated drug regimen (propofol in group P; remimazolam in group R; and remimazolam combined with propofol in group RP). General information, operation time and awakening time of the patients in the three groups were compared, as well as oxygen saturation (SpO2), heart rate (HR), mean arterial pressure (MAP), respiratory rate (RR), electroencephalography bifrequency index (BIS), and Ramsay's sedation score before anesthesia (T0), after anesthesia (T1), at the time of placement of the scope (T2), duodenal papillotomy (T3), and stenting or placement of a nasobiliary catheter (T4); the total number of intraoperative medication additions, number of somatic motions, and number of intestinal peristalsalsis; and the number of respiratory, cardiovascular-related adverse events and anesthesia-related postoperative complications were recorded and compared. RESULTS: There was no statistically significant difference in the general information, operation time, awakening time, Ramsay sedation score, surgeon, patient satisfaction and the incidence of anesthesia-related postoperative complications among the three groups (P>0.05). Compared with the P group, the R and RP groups had lower incidence of injection pain, hypotension, bradycardia and respiratory depression, and bile heart reflex; the post-anesthesia RR and BIS values were high, and the differences were statistically significant (P<0.05). Compared with the R group, the P and RP groups had less number of somatic and intestinal motility hyperactivity, and the difference was statistically significant (P<0.05). CONCLUSION: Remimazolam combined with propofol for ERCP anesthesia can be effective, the process is smooth, and the adverse reactions are few, which is worth to promote the application in the clinic.