Background: The ideal method for anaesthetic management during endoscopic retrograde cholangiopancreatography (ERCP) varies between deep sedation and general anesthesia with preference for general anesthesia over sedation. Objective: This study compares the effects of propofol-dexmedetomidine and propofol-ketamine combinations for anesthesia in patients having ERCP with respect to hemodynamic and respiratory parameters alterations as well as propofol requirements, recovery phase, and post-operative pain. Patients and methods: Patients, aged 20-50 years old, American Society of Anesthesiologists (ASA) І-II-III, were randomly allocated over a period of six months in 2 groups, each was 25. Group-I were administered dexmedetomidine loading 1 µg/kg slow IV over 15 minutes then infused at a rate of 0.5 µg/kg/h by syringe pump. Group II were administered Ketamine 1 mg/kg slow IV over 15 minutes then infused at a rate of 0.5 mg/kg/h by syringe pump. Results: The 2 groups had no significant differences as regards demographic data, ASA classification, time of the procedure, and baseline of hemodynamic data; heart rate (HR) and mean arterial blood pressure (MAP). Intra- and post-procedural dexmedetomidine-propofol group showed lower statistically significant differences as regards both heart rate and MAP. Post-procedural nausea, and cognitive disorders, were statistically significantly lower in dexmedetomidine-propofol group as well as recovery time was shorter. Conclusion: Dexmedetomidine-propofol combination was better compared with ketamine-propofol combination in terms of hemodynamic parameters (intra- and post-procedural), PONV, cognitive function and recovery time.