Background: Stress-related mental health problems negatively impact quality of life and productivity. Worldwide, treatment is often sought in primary care. Our objective was to determine whether a general practitioner-based minimal intervention for workers with stress-related sick leave (MISS) was cost-effective compared to usual care (UC). Methods: We conducted an economic evaluation from a societal perspective. Quality-adjusted life years (QALYs) and resource use were measured by the EuroQol and cost diaries, respectively. Uncertainty was estimated by 95% confidence intervals, cost-effectiveness planes and acceptability curves. Sensitivity analyses and ancillary analyses based on preplanned subgroups were performed. Results: No statistically significant differences in costs or QALYs were observed. The mean incremental cost per QALY was - €7356 and located in the southeast quadrant of the cost-effectiveness plane, whereby the intervention was slightly more effective and less costly. For willingness-to-pay (λ) thresholds from €0 to €100,000, the probability of MISS being cost-effective was 0.58-0.90. For the preplanned subgroup of patients diagnosed with stress-related mental disorders, the incremental ratio was - €28,278, again in the southeast quadrant. Corresponding probabilities were 0.92 or greater. Limitations: Non-significant findings may be related to poor implementation of the MISS intervention and low power. Also, work-presenteeism and unpaid labor were not measured. Conclusions: The minimal intervention was not cost-effective compared to usual care for a heterogeneous patient population. Therefore, we do not recommend widespread implementation. However, the intervention may be cost-effective for the subgroup stress-related mental disorders. This finding should be confirmed before implementation for this subgroup is considered. © 2009 Elsevier B.V. All rights reserved.