Objective: To compare the safety and efficacy of nalbuphine combined with propofol and fentanyl combined with propofol in patients undergoing endoscopic ultrasonography (EUS). Methods: A total of 100 patients of both sexes, aged 18–70 years, weighing 45–80 kg, of ASA physical status I or II, undergoing EUS were included in this study and randomly assigned to 2 groups (n=50 for each): a nalbuphine plus propofol (group N) or a general anesthesia (Fentanyl plus propofol, group F). The study protocol was approved by the institutional review board for human investigation of our hospital. In group F, fentanyl and propofol were administered according to following protocol: 1 μg/kg fentanyl was injected, and then 1–2 mg/kg propofol was given peripheral intravenously. The anesthesia was induced in group N with a similar manner: 0.1 mg/kg nalbuphine was injected and 1–2 mg/kg propofol were used. While body movement was observed during the endoscopic procedure, 0.2–0.5 mg/kg propofol was added. Outcomes measured included time of operation time, wake-up time, recovery time, occurrence of adverse cardiovascular events, bucking, nausea and vomiting and respiratory depression. The amount of propofol consumed was recorded. Results: No statistical difference was observed in time of operation time between the two groups. But, wake-up time, recovery time, adverse cardiovascular events, the incidence of bucking, the incidence and the degree of nausea and vomiting and respiratory depression, and amount of propofol consumed were significantly decreased in group N, compared with group F. Conclusion: A combination of nalbuphine and propofol is a better and safer way to induce anesthesia for patients undergoing EUS than fentanyl combined with propofol. It shows more stable hemodynamics, less respiratory inhibition, and fewer complications during and after EUS.