Objective: Demoralization is a commonly observed syndrome in cancer patients, deserving to be carefully assessed in cross-cultural contexts. Aims: To examine the factor structure and concurrent and divergent validity of the Italian version of the Demoralization Scale (DS-IT) in cancer patients. Methods: The sample included 194 Italian cancer outpatients who were assessed by using the DS-IT and the Diagnostic Criteria of Psychosomatic Research-Demoralization module to examine demoralization. The Patient Health Questionnaire-9 (PHQ-9) to explore depression and the Mini-Mental Adjustment-to-Cancer-Hopelessness/Helplessness scale (Mini-MAC-HH) to explore maladaptive coping were also administered. Results: Four factors were extracted by exploratory factor analysis on the DS-IT (disheartenment, α = .87; sense of failure, α = .77; dysphoria, α = .73; loss of meaning/purpose, α = .72; total = 0.91), accounting for 57.1% of the variance. The DS-IT factors shared between 17% and 36% of the variance. Patients reporting a diagnosis of demoralization on the Diagnostic Criteria of Psychosomatic Research-Demoralization module (23.7%) had higher scores on DS-IT loss of meaning/purpose, sense of failure, dysphoria, and DS-IT total. About half of those who were highly demoralized were not depressed and among those who had moderate or moderately severe demoralization, about 80% were not depressed on the PHQ-9. The DS-IT was significantly associated with PHQ-9 and Mini-MAC-HH. Conclusions: The study presents further evidence that demoralization is a significant clinical condition and that the DS-IT demonstrates satisfactory levels of validity and reliability to support its use in patients in the ambulatory cancer setting.