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.