OBJECTIVES: Many breast cancer patients suffer from (severe) menopausal symptoms after an early onset of menopause caused by cancer treatment. The standard treatment for these complaints is hormone replacement therapy, which, however, is contraindicated for this group, as it may have tumor-promoting effects. The aim of this study was to assess the cost-effectiveness of three interventions aimed at alleviating these symptoms: cognitive-behavioral therapy (CBT), physical exercise (PE), and the combination of both (CBT+PE). METHODS: A cost-effectiveness analysis was performed from a health care system perspective. The primary outcome was incremental health care costs (IHCC) per patient with a clinically relevant improvement after six months of treatments. The secondary outcome was incremental costs per quality-adjusted life years (QALYs) gained over a five-year time period. This was assessed using a Markov model, populated with data from a recent randomized controlled trial evaluating the effectiveness of CBT, PE, and CBT+PE in the clinical setting and additional cost data. The robustness of the results was analyzed through one-way and probabilistic sensitivity analyses. RESULTS: IHCCs for alleviating one patient of the perceived symptom burden by a clinically relevant difference after six months of treatment were EUR€605 for CBT, EUR€1,847 for CBT+PT, and EUR€1,250 for PE alone, compared to the waiting list control group. CBT generated 0.009 additional QALYs at an additional cost of EUR€162, compared to the control group, leading to an Incremental Cost Utility Ratio (ICUR) of EUR€18,655 per QALY gained and The ICUR of CBT+PE was EUR€42,375 per QALY in comparison to the control group. CBT had a high probability (circa 61%) of being cost-effective at prevailing ceiling ratios. CONCLUSIONS: CBT is likely the most cost-effective of the three interventions investigated for alleviating treatment-induced menopausal symptoms in breast cancer patients.