Model developed by Mark and Smith in 2008, the study aims to propose and test a multi-dimensional model that combines work characteristics, individual characteristics, and work-family interface dimensions as predictors of nurses' psychophysical health. Methods: Self-report questionnaires assessing work characteristics (effort; rewards; job demands; job control; social support), individual characteristics (socio-demographic characteristics; coping strategies; Type A behavioral pattern; Type D personality), work-family interface dimensions (work-family interrole conflict; job and life satisfaction), and health outcomes (psychological disease; physical disease) were completed by 450 Italian nurses. Logistic regression analyses and Hayes' PROCESS tool were used to test the proposed model by exploring main, moderating and mediating hypotheses. Results: Findings confirmed the proposed theoretical framework including work characteristics, individual characteristics, and work-family interface dimensions as significant predictors of nurses' psychophysical disease. Specific main, moderating and mediating effects were found, providing a wide set of multiple risks and protective factors. Conclusions: The study allowed a broader understanding of nurses' workrelated stress process, providing a comprehensive tool for the assessment of occupational health and for the definition of tailored policies and interventions in public healthcare organizations to promote nurses' wellbeing.