Abstract: Context: Ketamine is an emerging drug for the treatment of acute undifferentiated agitation in the prehospital environment, however no prospective comparative studies have evaluated its effectiveness or safety in this clinical setting. Objective: We hypothesized 5 mg/kg of intramuscular ketamine would be superior to 10 mg of intramuscular haloperidol for severe prehospital agitation, with time to adequate sedation as the primary outcome measure. Methods: This was a prospective open label study of all patients in an urban EMS system requiring chemical sedation for severe acute undifferentiated agitation that were subsequently transported to the EMS system’s primary Emergency Department. All paramedics were trained in the Altered Mental Status Scale and prospectively recorded agitation scores on all patients. Two 6-month periods where either ketamine or haloperidol was the first-line therapy for severe agitation were prospectively compared primarily for time to adequate sedation. Secondary outcomes included laboratory data and adverse medication events. Results: 146 subjects were enrolled; 64 received ketamine, 82 received haloperidol. Median time to adequate sedation for the ketamine group was 5 minutes (range 0.4–23) vs. 17 minutes (range 2–84) in the haloperidol group (difference 12 minutes, 95% CI 9–15). Complications occurred in 49% (27/55) of patients receiving ketamine vs. 5% (4/82) in the haloperidol group. Complications specific to the ketamine group included hypersalivation (21/56, 38%), emergence reaction (5/52, 10%), vomiting (5/57, 9%), and laryngospasm (3/55, 5%). Intubation was also significantly higher in the ketamine group; 39% of patients receiving ketamine were intubated vs. 4% of patients receiving haloperidol. Conclusions: Ketamine is superior to haloperidol in terms of time to adequate sedation for severe prehospital acute undifferentiated agitation, but is associated with more complications and a higher intubation rate.