OBJECTIVES: Lung cancers are the most common malignant tumours, accounting for 1.38 million annual deaths worldwide. Non-small cell lung cancer (NSCLC), the predominant tumour subtype, is associated with significant deteriorations in both survival and quality of life.  Epidermal growth factor receptor tyrosine kinase (EGFR-TK) has emerged as a drug therapy target.  The National Institute for Health and Care Excellence (NICE) recommends erlotinib – an EGFR-TK inhibitor – for first-line treatment of NSCLC in EGFR-TK mutation-positive patients, and second-line treatment in all patients irrespective of EGFR-TK mutations.  We developed a model to assess the cost-effectiveness of an EGFR-TK mutation status-guided treatment strategy for stage III/IV NSCLC, compared with a strategy not dependent on mutational status. METHODS: A Markov model was developed from the perspective of the UK National Health Service (NHS) over a lifetime horizon.  This compared a current scenario (in which a cohort of NSCLC patients received doublet chemotherapy at first-line therapy, followed either by erlotinib or docetaxel at second-line) to a revised scenario (in which all EGFR-TK mutation-positive patients received erlotinib at first-line followed by second-line docetaxel, and all mutation-negative patients received doublet chemotherapy followed by either docetaxel or erlotinib).  Efficacy data were based on the TORCH and TAX317 randomised controlled trials. Cost data were obtained from NHS Reference Costs, British National Formulary list prices and other publically-available sources. RESULTS: In the base-case analysis, the estimated incremental cost-effectiveness ratio exceeded the NICE willingness-to-pay threshold of £20,000 per quality-adjusted life year gained.  Univariate and probabilistic sensitivity analyses suggested the results were robust to parameter changes, showing greatest sensitivity to variation in overall survival parameters. CONCLUSIONS: Our model suggests that, from the perspective of the UK NHS, an EGFR-TK mutation status-guided treatment strategy across first- and second-line treatment of NSCLC is not cost-effective compared with a strategy not dependent on mutational status.