BACKGROUND Occupational skin diseases (OSDs) are the most common work-related diseases in Germany and responsible for a large individual and financial burden. Therefore, a tertiary individual prevention program (TIP) is offered to patients with severe OSD who are at increased risk of abandoning their profession. OBJECTIVE To define cost of illness (COI) of OSD in Germany and to economically evaluate the TIP from a societal perspective. METHODS In this study, data on patients taking part in the TIP (September 2005 to December 2009) were collected. Sociodemographic and medical data, costs, disease severity (Osnabrueck Hand Eczema Severity Index), and quality of life (QoL; Dermatology Life Quality Index) were assessed. COI and cost-effectiveness analyses were performed with a simulated control group. RESULTS In the analysis, 1041 patients were included. Intervention costs per person were €15 009 with decreasing COI over time. The incremental cost-effectiveness ratio revealed expenses per patient of €8942 for a reduction in severity level and €9093 for an improvement in QoL in the base case. Considering costs for retraining, the break-even point is reached if the TIP prevents retraining in approximately 64% of participants. CONCLUSIONS The decreased COI in this long-term evaluation indicates that the TIP is cost-effective in patients with severe OSD.