Background: The use of procedural sedation and analgesia to allow painful orthopaedic manipulations in the emergency department has become a standard practice over the last decade. Both propofol and midazolam/ketamine are attractive sedative regimens for routine use in the emergency department. We hypothesized that sedation with propofol as compared with midazolam/ketamine will save time in the emergency department. The purpose of the present study was to compare the recovery time, the total sedation time, and the adverse events of procedural sedation and analgesia induced with propofol as compared with midazolam/ketamine. Methods: This prospective randomized study was conducted in the emergency department of a tertiary care, universityaffiliated medical center. All sedations and orthopaedic manipulations were performed by trained and approved orthopaedic residents assisted by a registered nurse according to the same protocol. Sedation time and adverse events were recorded in real time. Results: Sixty adults (thirty-five men and twenty-five women) with a mean age (and standard deviation) of 45 ± 17 years were randomly enrolled in the study, with thirty patients being managed with each regimen. The average recovery time was 7.8 ± 3.7 minutes following sedation with propofol, compared with 30.7 ± 10.1 minutes following sedation with midazolam/ketamine (p < 0.001). The average total sedation time was 16.2 ± 3.8 minutes for the propofol group, compared with 41.6 ± 10.7 minutes for the midazolam/ketamine group (p < 0.001). The overall rate of respiratory and hemodynamic adverse events was 20% for the propofol group and 10% for the midazolam/ketamine group. Conclusions: The use of propofol for an orthopaedic procedure requiring sedation in the emergency department expedites patient management and saves time in comparison with the use of midazolam/ketamine. Level of Evidence: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.