To estimate the cost-effectiveness of cetuximab in combination with radiotherapy compared with radiotherapy alone, for the treatment of locally advanced head and neck cancer patients in Spain. A probabilistic Markov model (second-order Monte Carlo simulation) with a five-year time horizon and quarterly Markov cycles was performed from the perspective of the Spanish National Health System (NHS). The additional cost and quality-adjusted life-year (QALY) gain per patient receiving radiotherapy in combination with cetuximab compared with radiotherapy alone was €4356 (95% CI: €4350-4362) and 0.2380 (95% CI: 0.2370-0.2391) QALY, respectively. The incremental cost per QALY gain was €18,303 (95% CI: €18,243-18,354) with a probability of cost-effectiveness of 65.4% for a willingness to pay of €30,000 per QALY gained. According to the results of this analysis, the addition of cetuximab to radiotherapy would be a cost-effective alternative to radiotherapy alone in the treatment of locally advanced head and neck cancer in Spain.