The objective of this study was to compare the effectiveness and safety of intramuscular droperidol to other intramuscularly administered agents used in the management of acutely agitated patients. Twenty-seven inpatients with a history of brain injury were prospectively monitored over a period of 2 months. Data collected for each episode of agitation include: dose, number of doses, time to achieve an adequate response or calming effect, post-episodic functioning, treatment-emergent side effects, and other patient demographics. A retrospective medical records review was also performed on the same cohort, to compare clinical outcomes associated with other intramuscular agents previously used for acute agitation. Time to achieve calming was significantly shorter with intramuscular droperidol (mean = 27.0 minutes) compared to intramuscular haloperidol, lorazepam, or diphenhydramine (group mean = 36.2 minutes, p = 0.02). Of the three comparative agents, the time to achieve calming was the fastest with lorazepam (mean = 35.0 minutes), and slower with diphenhydramine (mean = 42.6 minutes) and haloperidol (mean = 43.0 minutes). Single doses of droperidol controlled agitation more frequently than did single doses of comparative agents, and there was less post-episodic sedation with droperidol following release from seclusion or restraints. Both groups were similar in regard to the incidence of treatment-emergent events. This data represents the first published experience supporting the effectiveness of droperidol in reducing acute agitation in persons with brain injury. Follow-up studies with prospective, double-blind, parallel treatment groups should be performed to validate these preliminary findings.