Aim: We aimed to assess the safety and efficacy of propofol versus midazolam in cirrhotic patients undergoing upper GI endoscopy. Methods: Ninety compensated cirrhotic patients (all met class I–III criteria according to the American Society of Anesthesia) were enrolled in this comparative study. They were classified into three groups according to scheduled pre-endoscopy sedation drugs; the midazolam group, which included 30 patients who received IV weight-dependent midazolam (0.05 mg/kg with additional doses of 1 mg every 2 min when necessary, up to a maximum dose of 0.1 mg/kg or 10 mg); the propofol group, which included 30 patients who received a propofol bolus dose according to age and weight (0.25 mg/kg with additional doses of 20–30 mg every 30–60 s when necessary, up to a maximum dose of 400 mg); and the combined group, which included 30 patients who received half a dose of midazolam and of propofol. Results: Prolonged postendoscopy recovery times were reported in the midazolam group, while shorter recovery times were reported in the propofol and combined groups. All patients in the propofol and combined groups gained consciousness shortly postendoscopy; however, only half of the midazolam group’s patients gained consciousness after the standard recovery time (10–30 min). Highly significant differences were found among the three groups regarding consciousness level according to the Glasgow coma scale, as well as regarding the occurrence of hypoxia during endoscopy. Conclusion: Considering safety and efficacy issues, propofol is better than midazolam in gastrointestinal endoscopy, especially in patients with liver cirrhosis