Abstract Purpose The Stress-Prevention@Work implementation strategy has been demonstrated to be successful in reducing stress in employees. Now, we assess the economic return-on-investment to see if it would make for a favourable business case for employers. Methods Data were collected from 303 health-care workers assigned to either a waitlisted control condition (142 employees in 15 teams) or to Stress-Prevention@Work (161 employees in 15 teams). Main outcome was productivity losses measured using the Trimbos and iMTA Cost questionnaire in Psychiatry. Measurements were taken at baseline, 6, and 12 months post-baseline. Results The per-employee costs of the strategy were €50. Net monetary benefits were the benefits (i.e., improved productivity) minus the costs (i.e., intervention costs) and were the main outcome of this investment appraisal. Per-employee net benefits amounted to €2981 on average, which was an almost 60-fold payout of the initial investment of €50. There was a 96.7% likelihood for the modest investment of €50 to be offset by cost savings within 1 year. Moreover, a net benefit of at least €1000 still has a likelihood of 88.2%. Conclusions In general, there was a high likelihood that Stress-Prevention@Work offers an appealing business case from the perspective of employers, but the employer should factor in the additional per-employee costs of the stress-reducing interventions. Still, if these additional costs were as high as €2981, then costs and benefits would break even. This study was registered in the Netherlands National Trial Register, trial code: NTR5527.