Background: Upper gastrointestinal endoscopy [either diagnostic or therapeutic] is widely practiced under conscious sedation. However, the standard sedative agent or drug combination is not yet well established. Aim of the work: Comparison between propofol-fentanyl and midazolam-fentanyl for sedation in upper gastrointestinal endoscopy. Patients and methods: Sixty patients from those scheduled to undergo upper gastrointestinal endoscopy at the Gastrointestinal Endoscopy Unit were included. Patients were divided into two equal groups: propofol-fentanyl and midazolam fentanyl. The Anesthetist scheduled to perform the procedures was oriented by the drug, while patients did not know the sedating drug. Prior to the procedure, a clinical history and physical examination was carried out, and throughout the procedure the patient was monitored for blood pressure, heart rate, respiratory rate, and oxygen saturation. Both groups were compared regarding time to recovery, patient satisfaction, physician satisfaction and adverse events. Results: Recovery time was significantly shorter, patient and physician satisfaction scores were significantly higher among propofol group. On the other side, systolic blood pressure was significantly lower in propofol group at midpoint and recovery times, while oxygen saturation was significantly reduced in midazolam group at intermediate point of the procedure. Finally, hypoxia was significantly higher among midazolam group [reported in 20.0%], versus [none] in propofol group. No other adverse events were encountered. Conclusion: Propofol is better sedative than midazolam for upper gastrointestinal endoscopy. Thus, it should be used as a first-line drug in sedation in our endoscopy units.