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Demoralization is a syndrome of existential distress that occurs in a substantial minority of cancer patients and is associated with a higher number of physical problems. Loss of dignity refers to a range of specific existential concerns. This study examines whether the association between number of physical problems and demoralization is mediated by loss of dignity.This cross-sectional study examinedN= 112 inpatients with mixed tumor sites at early and advanced disease stages using the following standardized self-report questionnaires: Physical problems list of the National Comprehensive Cancer Network (NCCN) Distress Thermometer (DT), Patient Dignity Inventory (PDI), Demoralization Scale (DS), Patient Health Questionnaire-9 (PHQ-9) and Illness-Specific Social Support Scale Short Version-8 (ISSS-8). The mediation hypothesis was tested by multiple regression analyses controlling for age, gender, curative versus palliative treatment phase, and social support.Patients reported M = 4.7 (SD = 6.0) dignity-related problems; 20% showed moderate to severe demoralization. Loss of dignity significantly mediated 81% of the effect of the number of physical problems on demoralization (Sobelzs = 4.4,p< .001). Testing the reverse direction, we found that demoralization mediated only 53% of the association between physical problems and loss of dignity (zs = 3.7,p< .001).By supporting the mediation hypothesis, our results indicate that loss of dignity partially explains the association between physical problems and demoralization. Early recognition of dignity-related existential concerns and interventions to enhance the sense of dignity may prevent demoralization in patients with cancer. Results provide a conceptual link between existential concerns (loss of dignity) and existential distress (demoralization) as two approaches to existential suffering in patients with cancer.