Purpose: Midazolam is fast-acting benzodiazepine, with anxiolytic, amnesic, hypnotic, anticonvulsant, muscle relaxant and sedative properties. It is used for sedation during diagnostic and therapeutic endoscopic procedures, but its sedative and amnestic effects are not sufficient for longer procedures such as ERCP. Opioids are added, but questions have been raised about benefit of this combination. Propofol is rapid acting anesthetic and has advantages over benzodiazepines and narcotics because of more rapid onset of action and rapid recovery to alertness without residual sedative effects or amnesia. Study was planned to investigate the effectiveness of Midazolam/Nalbuphine combination with Propofol for sedation during ERCP in terms of effectiveness of sedation, frequency of possible complications and quality of recovery from sedation. Methods: 60 patients were enrolled in two groups. Group A (n=30) received Midazolam (0.07mg/Kg body weight over 30 seconds and then increments given after every two min as needed) and Nalbuphine (2mg stat followed by 2mg every 5 min as needed). Group B (n=30) received Propofol Lipuro (1.5mg/Kg body wt) over 30 sec with 10 mg dosing after every two min as needed). Patient's BP, heart rate, R/R and 02 saturation were monitored preinduction and after every three min. ECG was monitored continuously. During recovery patients were assessed for duration of full orientation in time and place, and were interviewed after 10, 20, and 30 minutes. Aldrete scoring was used for this purpose. Results were analyzed using t-tests and one way analysis of variance (ANOVA). Fischer exact test was used to determine significance of changes from baseline in each group and differences between groups. Significant covariates were entered into a multivariate stepwise logistic regression model to identify those that contained independent information. P-value of < 0.05 was taken significant. Results: Both treatment groups were similar in age, gender, weight and for duration of procedure. Cardiopulmonary assessment revealed more fall of BP, R/R and rise of heart rate in Group A (p-value <0.05). Also there was more fall of 02 saturation in Midazolam group as compared to Propofol group (pvalue<0.05). Multivariate stepwise logistic regression analysis was done for patient's acceptability of procedure, which revealed higher level of patient comfort (x 2 = 5.3, p < 0.05), and a quicker patient recovery time (x2 = 19.5, p < 0.01; × 2 = 52.1, p <0.01; x2 = 58.4, p < 0.01 for Aldrete in 10 min, 20 min, and 30 min, respectively). Conclusion: Propofol as compared to Midazolam/Nalbuphine combination is well tolerated, has more acceptable and effective sedation and has early recovery from sedation.Table: Cardiopulmonary assessment (Midazolam)Table: Cardiopulmonary assessment (Propofol)