BACKGROUND AND AIMS Moderate to deep levels of sedation and analgesia are required for ERCP. Propofol-based sedation is simple, easy to use, and effective, but is not without cardiovascular and respiratory adverse effects. The combination of dexmedetomidine and ketamine (DK) has shown promising results for sedation in other similar scenarios. The aim of this study was to compare the efficacy and safety of a standard propofol-fentanyl (PF) regimen with a DK combination. METHODS After approval of the hospital ethics committee, 83 patients (18-75 years of age) were randomized and divided into 2 groups. Forty-two patients received a PF combination (group PF) and 41 patients received DK combination (group DK) for total intravenous anesthesia for ERCP as initial boluses followed by an infusion of PF and DK, respectively. The sedation-related adverse effects and recovery time were noted. RESULTS The mean values of the hemodynamic and respiratory parameters were in clinically acceptable ranges, but there were more episodes of hypotension (19%), bradycardia (4.7%), and decrease in oxygen saturation (Spo(2) <80% in 11.9% and Spo(2) <90% for >10 s in 42.8%) in group PF. The procedure could be completed in all of the patients but was interrupted in 6 patients in group PF because of desaturation (5) or sudden patient movement (1). The recovery time was longer in group DK than in group PF. CONCLUSION There were significantly fewer sedation-related adverse effects, but the recovery time was longer with DK.