Background and Study Aims: Patients undergoing colonoscopy are often sedated with benzodiazepines and long-acting opiates. Since low-dose midazolam also acts synergistically with short-acting propofol, we compared this synergistic sedation with a standard combination of midazolam and the opioid nalbuphine for colonoscopies. Patients and Methods: A total of 79 patients presenting for colonoscopies were randomly assigned to the following protocols. Patients in group I (n = 32) received a median dose of 9 mg midazolam (interquartile range [IQR] 6 to 12); 20 patients (59%) needed additional nalbuphine (median 20 mg, IQR 10 to 20). Patients in group II (n = 47) received 2 mg midazolam and repeated injections of propofol (median 100 mg, IQR 53 to 145) with a maximal bolus of 50 mg. Results: Patients treated with the synergistic sedation (group II) recovered remarkably sooner after the procedure compared with those in group I, with a median time to discharge of 17 minutes vs. 93 minutes (P < 0.001). Of the patients treated with analgosedation (group I), 28% were unable to take part in a reaction time measurement and attention awareness test 1 hour after the procedure. All patients treated with the synergistic sedation were able to participate (P = 0.002), and performed better. Despite a lower proportion of complete amnesia, patients treated with synergistic sedation more often rated the procedure as comfortable (81% vs. 50%). Quality of sedation from the point of view of the endoscopist, and cardiorespiratory parameters, were similar in both groups. Conclusions: Low-dose midazolam combined with propofol is an effective and economic alternative to benzodiazepine-based analgosedation. It is associated with a high degree of patient comfort and rapid recovery times, and has a potential cost benefit concerning nursing care and bed facilities.