Although non-invasive ventilation (NIV) is recommended in patients with chest trauma, this procedure may expose to discomfort and even failure due to agitation or excessive pain. We tested the impact of dexmedetomidine on the duration of the first session of NIV. This randomised, crossover study enrolled 19 patients with blunt chest trauma who needed NIV. During one cycle comprising two NIV sessions, patients received in a random order an intravenous infusion of dexmedetomidine (0.7mcg/kg/h) and placebo (saline solution) that was initiated 60min prior to NIV. Dexmedetomidine (or placebo) was titrated to maintain a Richmond Agitation Sedation Scale (RASS) score between 0 and −3. A 6-h washout period was observed between NIV sessions. The reproducibility of the drug-related effects was tested during a second cycle of two NIV sessions. During the first cycle, dexmedetomidine prolonged the duration of NIV compared to placebo: 280min (118–450) (median, 25–75th quartiles) versus 120min (68–287) respectively, corresponding to a median increased duration of 96min (12–180) (P=0.03). Dexmedetomidine was associated with a lower score for RASS: −0.8 (−1.0;0.0) versus 0.0 (−0.5;0.0) (P<0.01), and reduced respiratory discomfort according to the 10cm visual similar scale: 0.6cm (0.0–3.0) versus 2.2cm (0.0–5.3) (P=0.05). Pain scores, morphine consumption, and blood gas measurements were comparable between groups. No difference in the duration of non-invasive ventilation was found during the second cycle. In this pilot trial, dexmedetomidine could facilitate the acceptance of the first session of non-invasive ventilation for patients with chest trauma.