Definitive radiotherapy is the current standard of care for patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) who are contraindicated and/or not able to tolerate the severe acute and late toxicities associated with concomitant chemoradiotherapy. Cetuximab (cetuximab) in combination with radiotherapy has been shown to significantly improve patient outcomes when compared to radiotherapy alone without aggravating the side effects of radiotherapy. OBJECTIVE: To estimate the cost-effectiveness of Cetuximab in combination with radiotherapy (ERT) compared to radiotherapy alone (RT), for the treatment of locally advanced head and neck cancer in patients for whom chemoradiotherapy is inappropriate or intolerable in Spain. METHODS: A decision-analytic model was used to estimate the clinical and economic consequences of locally advanced SCCHN. Model parameters and health resources use were derived from an international phase III clinical trial. Costs were obtained from local data and validated by local clinical experts. Effectiveness was measured as progression-free survival (PFS) and QALYs gained and extrapolated beyond trial follow-up. Costs and outcomes were discounted at an annual rate of 3%. RESULTS: ERT was associated with an incremental effectiveness of 1.17 years free of disease progression and 0.97 QALYs, and with additional cost per patient of about €8777 resulting in incremental cost-effectiveness ratios of €7532 per progression-free life years and €9091 per QALY gained. The probabilistic sensitivity analysis showed that the probability of ERT being cost-effective at the accepted cost-effectiveness threshold in Spain of €30,000 per QALY is over 99%. CONCLUSIONS: Cetuximab added to radiotherapy is a cost-effective option compared to radiotherapy alone, with better outcomes at a reasonable additional cost. Its clinical and pharmacoeconomic profile makes Cetuximab + radiotherapy the optimal treatment for a significant proportion of patients with locally advanced SSCHN who are unable to tolerate or are contra-indicated to Chemo-Radiotherapy.