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Background Vitality refers to an organism’s inherent energy that supports adaptive functioning and well-being. Both frailty and depressive disorders are characterized by energy depletion and are commonly associated with fatigue, reduced subjective well-being, and impaired quality of life. Assessing vitality may serve as a complementary approach to identify conditions associated with energy depletion, while offering clinically meaningful information beyond that captured by disorder-specific measures alone. The Integrative Vitality Scale (IVS) measures the physical and psychological dimensions of vitality. This study examined the clinical validity of the IVS in frailty and depressive disorders. Methods Data were drawn from two independent South Korean samples: adults aged ≥65 years assessed for frailty (Study 1) and adults aged ≥19 years assessed for depressive disorders (Study 2). Correlation analysis was used to examine the associations between IVS scores and fatigue, subjective well-being, and quality of life. Receiver operating characteristic (ROC) curve analysis was used to evaluate screening performance against structured clinical interview-based reference standards. Hierarchical regression analyses were used to test the incremental explanatory value of the IVS beyond the established measures of frailty and depression. Results The IVS total and subscale scores were negatively associated with frailty, depressive symptoms, and fatigue, and positively associated with subjective well-being and quality of life. Physical vitality demonstrated good screening performance, with overall discriminative ability in a similar range to that of a clinician-rated frailty measure. For depressive disorders, the IVS total score showed fair screening performance, with overall discriminative ability in a similar range to that of the widely used self-report depression scale. Hierarchical regression analyses further indicated that the IVS explained additional variance in fatigue, subjective well-being, and quality of life beyond the established measures of frailty and depressive symptom severity, with physical vitality primarily related to fatigue, and psychological vitality being more strongly related to well-being and quality of life. Conclusion The IVS demonstrated clinical validity as a self-report screening and assessment tool for conditions characterized by energy depletion. Beyond initial screening, the IVS provides patient-centered information on functional status that is not fully captured by disorder-specific measures, supporting its complementary role in clinical screening contexts. Further validation in representative and community-based samples is required before broader public health applications can be considered. Clinical trial registration https://cris.nih.go.kr/cris/search/detailSearch.do?seq=27011&status=5&seq_group=27011&search_page=M , identifier KCT0009372; https://cris.nih.go.kr/cris/search/detailSearch.do?seq=26780&status=5&seq_group=26780&search_page=M , identifier KCT0009263.