Abstract Background Non-invasive ventilation (NIV) tolerance is a key factor of NIV success. Hence, numerous sedative pharmacological or non-pharmacological strategies have been assessed to improve NIV tolerance. Music therapy in various health care settings has shown beneficial effects. In invasively ventilated critical care patients, encouraging results of music therapy on physiological parameters, anxiety, and agitation have been reported. We hypothesize that a musical intervention improves NIV tolerance in comparison to conventional care. We therefore question the potential benefit of a receptive music session administered to patients by trained caregivers (“musical intervention”) to enhance acceptance and tolerance of NIV. Methods/design We conduct a prospective, three-center, open-label, three-arm randomized trial involving patients in the intensive care unit (ICU) who require NIV, as assessed by the treating physician. Participants are allocated to a “musical intervention” arm (“musical intervention” applied during all NIV sessions), to a “sensory deprivation” arm (sight and hearing isolation during all NIV sessions), or to the control group. The primary endpoint is the change in respiratory comfort (measured with a digital visual scale) before the initiation and after 30 minutes of the first NIV session. The evaluation of the primary endpoint is performed blindly from the treatment group. Secondary endpoints include changes in respiratory and cardiovascular parameters during NIV sessions, the percentage of patients requiring endotracheal intubation, day-90 anxiety/depression and health-related quality of life, post-trauma stress induced by NIV, and the overall assessment of NIV. The follow-up for each participant is 90 days. We expect to randomize a total of 99 participants. Discussion As music intervention is a simple and easy-to-implement non-pharmacological technique, efficacious in reducing anxiety in critically ill patients, it appeared logical to assess its efficacy in NIV, one of the most stressful techniques used in the ICU. Patient centeredness was crucial in choosing the outcomes assessed. Trial registration ClinicalTrials.gov: NCT02265458 . Registered on 25 August 2014.