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Purpose: The diagnosis of a terminal disease bears existential challenges, which activate the attachment system. Attachment insecurity, as well as existential resources, such as spiritual well-being, influences patients' extent of psychological distress. Knowledge about the interrelation of these constructs is limited. Based on current research, we assume spiritual well-being to mediate the association of attachment insecurity and psychological distress.Methods: We obtained data from the baseline measurement of a randomized controlled trial in advanced cancer patients. Patients were sampled from the University Medical Centers of Hamburg and Leipzig, Germany. Main outcome measures included the Patient Health Questionnaire (PHQ-9), the Death and Dying Distress Scale (DADDS), the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being Scale (FACIT-Sp), and the Experience in Close Relationships Scale (ECR-M16) for assessing attachment insecurity. We tested the mediation hypothesis with two regression analyses using bootstrapping procedure.Results: A total of 190 patients were included. Spiritual well-being mediated the association of attachment insecurity and depression (R2 = 11%), as well as death anxiety (R2 = 15%), in fearful-avoidant attached patients. Neither dismissingly nor preoccupied attached patients differ in terms of spiritual well-being and psychological distress in comparison with secure attached patients.Conclusion: Spiritual well-being plays a relevant role in advanced cancer patient's mental health through mediating the association of attachment and psychological distress. Developing a better understanding of the interdependency of the constructs of spiritual well-being and attachment can help to develop individually tailored advanced cancer care programs and psychotherapeutic interventions.Trial Registration: NCT02051660. [ABSTRACT FROM AUTHOR]