Background Remimazolam is a newer benzodiazepine with properties of rapid onset, short duration of action, and fast recovery. Our study was to evaluate the effects of different doses of remimazolam combined with alfentanil in colonoscopic polypectomy. Methods One hundred twenty patients were randomly divided into four groups: alfentanil and propofol (AP) group, alfentanil and remimazolam 0.1 mg/kg (AR1 group), 0.15 mg/kg (AR2 group), or 0.2 mg/kg (AR3 group). Patients in the four groups received alfentanil 10 mu g/kg, followed by propofol 2 mg/kg and three dosages of remimazolam. Modified Observer's Assessment of Alertness and Sedation (MOAA/S) scale, heart rate (HR), oxygen saturation (SpO(2)), respiratory rate (RR), bispectral index (BIS) values and mean arterial pressure (MAP) were collected at intervals of 5 min and analyzed at different time points: before anesthesia (T0), 5 min (T1), 10 min (T2), 15 min after anesthesia (T3) and at the end of surgery (T4). The average MAP was calculated utilizing the average of all MAP values. The primary outcome was the success rate of sedation. Secondary outcomes included time to full alert and adverse events. Results The success rate of sedation was 100% among the four groups. The incidence of hypotension was significantly decreased (all P < 0.05) and the average MAP was higher in AR1-AR3 groups than AP group (all P < 0.001). None of the patients developed bradycardia or hypertension during surgery in all study groups. BIS values were higher (all P < 0.001) and the time to full alert was statistically shorter in AR1-AR3 groups (all P < 0.05) compared with the AP group. The MOAA/S score in AR1 was higher than AR2 (P < 0.05) and the AR3 group (P < 0.05) at T1 and BIS values in the AR1 group were significantly higher than AR3 group (P < 0.05) at T4. Conclusions Remimazolam combined with alfentanil have a non-inferior sedative effect than propofol during the colonoscopic polypectomy. Moreover, this combination of two short-acting drugs might be a safer alternative.