Demoralization is a commonly observed syndrome in medically ill patients. The risk of demoralization may increase in patients after a kidney transplant (KTRs) because of the stressful nature of renal transplantation, psychosocial challenges, and adjustment needs. No study is available on demoralization amongst KTRs. The purpose of our study was to evaluate the validity of the Italian version of the Demoralization Scale (DS-IT) and the prevalence of demoralization in KTRs. Also, we aimed at exploring the association of the DS-IT with International Classification of Diseases (ICD) psychiatric diagnoses, post-traumatic growth (PTG), psychological and physical symptoms, and daily-life problems. A total of 134 KTRs were administered the MINI International Neuropsychiatric Interview 6.0. and the Diagnostic Criteria for Psychosomatic Research-Demoralization (DCPR/D) Interview. The DS-IT, the Edmonton Symptom Assessment System (ESAS), the Canadian Problem Checklist (CPC), were used to measure demoralization, physical and psychological symptoms, and daily-life problems; also, positive psychological experience of kidney transplantation was assessed with the PTG Inventory. Routine biochemistry and sociodemographic data were collected. Exploratory factor analysis demonstrated a four-dimensional factor structure of the DS-IT, explaining 55% of the variance (loss of meaning and purpose, disheartenment, dysphoria, and sense of failure). DS-IT Cronbach alpha coefficients indicated good or acceptable level of internal consistency. The area under the Receiving Operating Characteristics (ROC) curve for DS-IT (against the DCPR/D interview as a gold standard) was 0.92. The DS-IT optimal cut-off points were >= 20 (sensitivity 0.87, specificity 0.82). By examining the level of demoralization, 14.2%, 46.3%, 24.6%, and 14.6% of our sample were classified as having no, low, moderate, and high demoralization, respectively, with differences according to the ICD psychiatric diagnoses (p<0.001). DS-IT Total and subscales scores were positively correlated with scores of ESAS symptoms and CPC score. A correlation between DS-IT loss of meaning and purpose subscale and PTGI appreciation of life subscale (p<0.05) was found. This study shows, for the first time, a satisfactory level of reliability of the DS-IT and a high prevalence of severe demoralization in KTRs.