Objectives:  A phase III randomized trial that compared the combination of cetuximab and radiotherapy to radiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck provided a platform for a comprehensive economic evaluation. The study was conducted to estimate the cost-effectiveness of cetuximab in combination with radiotherapy compared to radiotherapy alone, for the treatment of locally advanced head and neck cancer in patients for whom chemoradiotherapy is inappropriate or intolerable.Methods:  Separate economic analyses were conducted for Belgium, France, Italy, Switzerland, and the United Kingdom. The economic model was based on individual patient data extracted from an international phase III trial. Country-specific costs of care from official sources were applied in each analysis. Clinical expert panels supplemented resource use estimates from the phase III trial and validated assumptions used to extrapolate costs and health outcomes beyond the follow-up of the phase III trial.Results:  In the base-case analysis, the incremental cost per quality-adjusted life-year for patients receiving radiotherapy in combination with cetuximab compared to radiotherapy alone among all countries was in the range of €7538 to €10,836. Sensitivity analysis showed the results to be robust.Conclusion:  This cost-effectiveness analysis indicated that the addition of cetuximab to high-dose radiotherapy offers a good value-for-money alternative to radiotherapy alone in the treatment of locally advanced head and neck cancer in five European countries.