OBJECTIVES: To compare the cost-effectiveness of therapy with erlotinib (ERL), docetaxel (DOC), pemetrexed (PEM) or best supportive care (BSC) in patients with advanced non-small cell lung cancer (NSCLC) in Spain. METHODS: A Markov model with 3 health states (progression free, disease progression and dead) was developed. Time horizon: 2 years (monthly cycles). Survival and time to progression were obtained from 3 clinical trials. Utilities were obtained from a study performed in UK in154 patients. National Health System (NHS) perspective (direct health costs) was applied. Resources used were estimated from a panel of Spanish oncologists and from the literature. Unit costs were derived from Spanish databases (€ march 2006). Annual discount rate: 3.5% (costs and utilities). Sensitivity analyses for subpopulations, 3 years results (Weibull and Loglogistic distributions) and probabilistic (Monte Carlo) were performed. RESULTS: After 2 years more QALY per patient were obtained with ERL (0.24) than with DOC (0.23) and BSC (0.18). No differences versus PEM were observed. The total cost per patient was lower with ERL (€17,838) than with DOC (€20,392; €-2,554) or PEM (€27,317; €-9,479) and higher than with BSC (€8,198; €+9,640). ERL was the “dominant” treatment (more efficacy and lower costs) versus DOC and resulted in a cost saving versus PEM. Additional cost per QALY or life year gained with ERL versus BSC: €160,667 and €56,706, respectively. The sensitivity analysis confirmed the robustness of the base case analysis. If 1,000 NSCLC patients were treated with ERL, the annual saving for NHS (substitution rates: 5%-65%) would range between €123,000-€1,600,000 (DOC replacement) and €448,000-€5,831,000 (PEM replacement). CONCLUSION: According to this model, advanced NSCLC treatment with ERL is more cost-effective than with DOC and PEM, with savings for the NHS.