OBJECTIVES: To assess the cost-effectiveness of Afatinib vs. comparators in the first-line treatment for patients with non-small cell lung cancer (NSCLC) harbouring epidermal growth factor receptor (EGFR) mutations. METHODS: A cost-effectiveness model was applied to assess the costs and effects of afatinib. Data related to medical resource use, efficacy of the drugs and health related quality-of-life status came from the clinical studies and supported by the results of a Network Meta-Analysis (NMA). Direct cost data was obtained from the Bureau of National Health Insurance (BNHI) and NHI claims data released by the Collaboration Center of Health Information Application. Outcomes included life-years, quality-adjusted life years (QALYs), medical costs and incremental cost-effectiveness ratios (ICERs). The single-payer (BNHI) perspective is assumed and costs are expressed in New Taiwan dollars (NT$). The discount rate of costs and effects is 5%. RESULTS: Treatment with afatinib in the 1st line setting extends time in progression-free survival (PFS). Compared to gefitinib, patients treated with afatinib in the 1^st line setting have an increase of 0.05 quality-adjusted life-years (QALYs) and the additional cost is NT$21,350.59, yielding an ICER of NT$457,768.67 per QALY gained. Compared to erlotinib, patients treated with afatinib have an increase of 0.02 QALYs with less cost of NT$-56,216. CONCLUSIONS: The results provide decision makers with information about the cost-effectiveness of taking afatinib as first-line therapy for advanced stage NSCLC by direct comparison of two EGFR-TKIs and cisplatin/pemetrexed. From the perspective of the single payer, the afatinib could be a cost-effectiveness strategy compared with erlotinib and gefitinib for the 1^st line treatment of advanced NSCLC.