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Background and Aims: Even though patient tolerance is critical to the success of noninvasive ventilation (NIV), research on using sedation to improve tolerance to NIV after traumatic chest injuries is limited. We hypothesized that dexmedetomidine would be superior to ketamine in terms of patient tolerance and lengthening the NIV sessions after blunt chest trauma. Material and Methods: This randomized, double-blinded, placebo-controlled trial included 45 patients of both genders aged 18–60 who needed NIV after blunt chest trauma. The patients were randomly assigned to one of three groups (n = 15) for receiving dexmedetomidine, ketamine, or placebo (0.9% sodium chloride solution) infusion to maintain a Richmond Agitation Sedation Scale (RASS) score between 0 and − 3 during two successive NIV sessions. Patients were evaluated for the duration of the NIV sessions, RASS, Visual Analog Scale (VAS), and the total amount of rescue analgesia consumed. Results: The mean duration of the NIV sessions was significantly longer in patients who received dexmedetomidine (P < 0.001) or ketamine (P < 0.001) compared to placebo. However, the NIV durations did not differ significantly between the dexmedetomidine and ketamine groups (P > 0.05). The dexmedetomidine group had a significantly lower RASS score compared to the ketamine (P < 0.001) and placebo (P < 0.001) groups, whereas the ketamine group had a significantly lower VAS compared to the dexmedetomidine (P = 0.005) and placebo (P = 0.022) groups and required significantly less total morphine (P = 0.001) compared to the other groups. Conclusion: The duration of the NIV sessions for patients with blunt chest trauma did not differ significantly between the dexmedetomidine and ketamine groups.