Objective To investigate the clinical effect of remimazolam combined with different opioids and remimazolam used alone and to expolre the rational compatibility of remimazolam in painless gastroscopy. Methods One hundred and sixty ASAⅠ or Ⅱ patients of both sexes, aged 18-64 yr, with BMI of 18-30 kg/m2, scheduled for painless gastroscopy in our hospital from November to December 2020, were selected and divided into 4 groups (n=40) using a random number table method: remimazolam combined with fentanyl group (group PF), sufentanil group (group PS), remifentanil group (group PR) and Remimazolam used alone group (group P). In group P, remimazolam 0.3mg/kg was injected intravenously. In PF, PS and PR groups, after fentanyl 50ug, sufentanil 0.1ug/kg and remifentanil 0.25ug/kg were intravenously injected, 0.3mg/kg remimazolam was intravenously injected within 60s. Gastroscopy was performed when MOAA/S＜2. MAP, HR and SpO2 will be recorded before anesthesia induction (T0), immediately after entering the endoscope (T1), 3min after entering the endoscope (T2) and 5min after entering the endoscope (T3). The gastroscopy time, recovery time and discharge time, The success rate of the first dose of sedation, the incidence of intraoperative adverse reactions, The satisfaction of endoscopists and patients with anesthesia and patients' willingness to accept the same sedation method in the future were interviewed at the end of surgery. Results Heart rate was significantly higher at T1 and MAP was significantly lower at T2 in group P than in groups PF, PS and PR (P 0.05). Compared with group P, the success rate of sedation at the first dose was significantly higher, the operation time was significantly shorter, the incidence of body movement and bucking was significantly lower, and endoscopists were more satisfied in PF, PS and PR groups (P 0.05). Compared with group PF, the bucking was significantly lower in group PR (P 0.05). Compared with group PR, the time of discharge was significantly prolonged in groups P, PF and PS (P 0.05). There was no others significant difference between the groups (P＞0.05) . Conclusion Remimazolam combined with opioids for painless gastroscopy can significantly improve the success rate of sedation and reduce adverse reactions than remimazolam used alone, and remimazolam combined with remifentanil is the best scheme for painless gastroscopy.