Live music therapy provided by a board-certified music therapist reduces anxiety, decreases pain, and improves the physiological response of patients in the intensive care unit (ICU). To examine the effect of live music therapy on the physiological parameters and pain and agitation levels of adult ICU patients receiving mechanical ventilation. A total of 118 patients were randomly assigned to live music therapy or standard care. The music therapy group received 30 minutes of live music therapy tailored to each patient's needs. The Richmond Agitation-Sedation Scale and the Critical Care Pain Observation Tool were completed by critical care nurses immediately before and after each session, and the patients' heart rates, respiratory rates, and oxygenation levels were measured. Patients who received live music therapy had significantly different scores on the Richmond Agitation-Sedation Scale (P < .001) and the Critical Care Pain Observation Tool (odds ratio, 6.02; P = .002) compared with the standard care group. Significant differences between groups were also reported in heart rate (P < .001). No significant differences were found in oxygen values. Live music therapy significantly reduced agitation and heart rate in adult patients receiving mechanical ventilation in the ICU. These findings provide further evidence for the benefits of music therapy in the ICU, including in intubated patients.