Study Objective: Acute behavioral disturbance is a common problem for emergency medical services. We aimed to investigate the safety and effectiveness of droperidol compared to midazolam in the prehospital setting. Methods: This was a prospective before and after study comparing droperidol to midazolam for prehospital acute behavioral disturbance, when the state ambulance service changed medications. The primary outcome was the proportion of adverse effects (airway intervention, oxygen saturation < 90%, respiratory rate < 12, systolic blood pressure < 90 mmHg, sedation assessment tool score −3 and dystonic reactions) in patients receiving sedation. Secondary outcomes included time to sedation, requirement for additional sedation, staff and patient injuries, and prehospital time. Results: There were 141 patients administered midazolam and 149 patients administered droperidol in the study. Alcohol was the most common cause of acute behavioral disturbance. Fewer patient adverse events occurred with droperidol (11/149) compared to midazolam (33/141) (7% vs. 23%; absolute difference 16%; 95% confidence interval [CI]: 8% to 24%; p = 0.0001). Median time to sedation was 22 min (interquartile range [IQR]:18 to 35 min) for droperidol compared to 30 min (IQR:20 to 45 min) for midazolam. Additional prehospital sedation was required in 6/149 (4%) droperidol patients and 20/141 (14%) midazolam patients, and 11 (7%) droperidol and 59 (42%) midazolam patients required further sedation in the emergency department. There were no differences in patient or staff injuries, or prehospital time. Conclusions: The use of droperidol for acute behavioral disturbance in the prehospital setting is associated with fewer adverse events, a shorter time to sedation, and fewer requirements for additional sedation.