© The Author(s) 2014. Objective: Patients suffering from moderate to severe serotonin syndrome frequently present with autonomic instability and altered mental status. Management of serotonin syndrome can be complex and may be refractory to treatment with benzodiazepines alone. The objective of this series is to present 3 cases of serotonin syndrome that demonstrated clinical improvement with initiation of dexmedetomidine. Case Series: We present 3 cases of severe serotonin syndrome in adolescents requiring intubation that were refractory to midazolam and/or propofol. Dexmedetomidine, an α-2 receptor agonist, was used in all 3 cases with temporal stabilization of the autonomic nervous system and improvement of agitation, and aided in successful extubation. Discussion: Although no human studies exist, rat and mouse models offer evidence that dexmedetomidine can reduce serotonin excess and stabilize signs of serotonin neurotoxicity. Conclusion: Accordingly, health care providers may consider using dexmedetomidine as adjunctive therapy for cases of severe serotonin syndrome that are refractory to standard treatment.