BACKGROUND: Although patients in palliative care commonly report high emotional and spiritual needs, effective psychosocial treatments based on high quality studies are rare. First research provides evidence for benefits of psychosocial interventions in advanced cancer care. To specifically address end-of-life care requirements, life review techniques and creative-arts based therapies offer a promising potential. Therefore, the present study protocol presents a randomized controlled trial on the effectiveness of a newly developed music therapy technique that is based on a biographically meaningful song ("Song of Life"; SOL). METHODS: In a design with two parallel arms, 104 patients at two palliative care units will be randomly assigned to three sessions of either SOL (experimental group) or relaxation exercises (control group). Improvements in the psychological domain of quality of life will be the primary endpoint, while secondary outcomes encompass spiritual well-being, ego-integrity, overall quality of life, and distress. Additionally, caregivers will be asked to provide feedback about the treatment. Assessment of biopsychological stress markers and qualitative analysis of perceived strengths and weaknesses will complement data collection. DISCUSSION: Based on the results of a previous pilot study, we dedicated considerable efforts to optimizing the intervention and selecting appropriate outcomes for the present trial. We are confident to have designed a methodologically rigorous study that will contribute to the evidence-base and help to develop the potential of psychosocial interventions in palliative care. TRIAL REGISTRATION: German Clinical Trials Register (DRKS) – DRKS00015308 (date of registration: September 07th 2018).