The aim of this study was to evaluate the cost-effectiveness of a multifaceted implementation strategy for the prevention of hand eczema in comparison with a control group among healthcare workers. A total of 48 departments (n=1,649) were randomly allocated to the implementation strategy or the control group. Data on hand eczema and costs were collected at baseline and every 3 months. Cost-effectiveness analyses were performed using linear multilevel analyses. The probability of the implementation strategy being cost-effective gradually increased with an increasing willingness-to-pay, to 0.84 at a ceiling ratio of €590,000 per person with hand eczema prevented (societal perspective). The implementation strategy appeared to be not cost-effective in comparison with the control group (societal perspective), nor was it cost-beneficial to the employer. However, this study had some methodological problems which should be taken into account when interpreting the results.