Objectives: Nurses are at elevated risk of burnout, anxiety and depressive disorders, and may then become less productive. This begs the question if a preventive intervention in the work setting might be cost-saving from a business perspective. Material and Methods: A cost-benefit analysis was conducted to evaluate the balance between the costs of a preventive intervention among nurses at elevated risk of mental health complaints and the cost offsets stemming from improved productivity. This evaluation was conducted alongside a cluster-randomized trial in a Dutch academic hospital. The control condition consisted of screening without feedback and unrestricted access to usual care (N = 206). In the experimental condition screen-positive nurses received personalized feedback and referral to the occupational physician (N = 207). Results: Subtracting intervention costs from the cost offsets due to reduced absenteeism and presenteeism resulted in net-savings of 244 euros per nurse when only absenteeism is regarded, and 651 euros when presenteeism is also taken into account. This corresponds to a return-on-investment of 5 euros up to 11 euros for every euro invested. Conclusions: Within half a year, the cost of offering the preventive intervention was more than recouped. Offering the preventive intervention represents a favorable business case as seen from the employer’s perspective.