Invasive endoscopic procedures such as total colonoscopy result in a better patient acceptance, the less discomfort they cause. Therefore a premedication for total colonoscopy is often required. In a prospective, double-blind, placebo-controlled clinical study of 132 patients examined by one experienced endoscopist we compared two premedication schedules: midazolam (mean 5.2 mg i.v.) versus midazolam (mean 4.8 mg) plus pethidin (50 mg). We found that the combination midazolam plus pethidin provides a deeper and more reliable sedation and analgesia than midazolam alone. The combination of both drugs caused also more anterograde amnesia. It was also shown, that the endoscopist scored a higher degree of patient's pain during the examination than the patient did himself. No more negative side-effects such as decrease of arterial partial pressure of oxygen or cardiopulmonary complications were found using the combination of both drugs; they provided to be safe without added risk of hypoxia. Thus, the combination of both drugs can be given as premedication for total colonoscopy.