Background: Knowledge and skill about sedation of aggressive patients is necessary for each psychiatrist. The purpose of this study was comparing the velocity and durability of sedation induced by the haloperidol, trifluoperazine, promethazine, and chlorpromazine in aggressive patients. Materials and Methods: This randomized clinical trial was done on 76 aggressive patients referred to Psychiatry Emergency Service of Noor Hospital of Isfahan University of Medical Sciences that were randomly divided into four groups of haloperidol, promethazine, chlorpromazine, and trifluoperazine. Patients were evaluated at 30 min intervals for aggressive symptoms, and if they did not respond to intervention after the first 30 min or if they showed aggression again, a same dose of the injected drug was prescribed. The length of sedation time was recorded for each patient. Results: Seventy-six patients with the mean age of 31.89 ± 8.73 years were participated and 63.2% of them were male. Response to intervention after the first injection was seen in 40.8% and 59.2% needed the second injection. The mean time needed for obtaining sedation was 17.38 ± 8.23 and 19.66 ± 4.64 min after the first and second injection, respectively. The mean times of sedation induction were not significantly related to age, gender, type of substance used, type of aggression, and type of psychiatric disorder. Considering the type of drugs, there was no significant difference between velocity and durability effect of sedation after the first and second injection. Conclusion: Comparing the velocity and durability of sedative effect of the four studied drugs on acute aggressive patients, did not show any significant difference between them.