The Demand Resources and Individual Effects Model (DRIVE Model) is a transactional model that integrates Demands- Control-Support and Effort-Reward Imbalance models emphasising the role of individual (Coping Strategies; Overcommitment) and job characteristics (Job Demands, Social Support, Decision Latitude, Skill Discretion, Effort, Rewards) in the work-related stress process. The present study aimed to test the DRIVE Model in a sample of 450 Italian nurses and to compare findings with those of a study conducted in a sample of UK nurses. A questionnaire composed of Ways of Coping Checklist-Revised (WCCL-R); Job Content Questionnaire (JCQ); ERI Test; Hospital Anxiety and Depression Scale (HADS) was used. Data supported the application of the DRIVE Model to the Italian context, showing significant associations of the individual characteristics of Problem-focused, Seek Advice and Wishful Thinking coping strategies and the job characteristics of Job Demands, Skill Discretion, Decision Latitude, and Effort with perceived levels of Anxiety and Depression. Effort represented the best predictor for psychological health conditions among Italian nurses, and Social Support significantly moderated the effects of Job Demands on perceived levels of Anxiety. The comparison study showed significant differences in the risk profiles of Italian and UK nurses. Findings were discussed in order to define focused interventions to promote nurses’ wellbeing.