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Highlights • Afatinib as first line treatment yielded the greatest health outcomes. • Afatinib is a cost-effective strategy for lung cancer in the Chinese context. • The survival benefits of afatinib had the substantial impact on the model outcome. Abstract Purpose Tyrosine kinase inhibitors (TKI) of the epidermal growth factor receptor (EGFR) are becoming the standard treatments for Chinese patients with advanced non-small cell lung cancer (NSCLC) harboring an EGFR mutation. However, the economic impact is unclear yet in China. Materials and methods A decision-analytic model was developed to simulate 1-month patient transitions in a 10-year time horizon from Chinese heath care system perspective. The health and economic outcomes of four first-line strategies (pemetrexed plus cisplatin [PC], gefitinib, erlotinib, and afatinib) among NSCLC patients harboring EGFR mutations were estimated and assessed via indirect comparisons. Costs in the Chinese setting were estimated by using local hospital data and literatures. A 5% annual discount rate was applied to both costs and outcomes. The primary outcome was the incremental cost-effectiveness ratio (ICER). Sensitivity analyses were performed. Results Afatinib achieved additional 0.382, 0.216 and 0.174 quality-adjusted life-years (QALYs) with marginal $7930, $3680 and $2818 costs in comparison with PC, gefitinib and erlotinib, which resulted in the ICERs of $20,758, $17,693 and $16,197 per QALY gained, respectively. The hazard ratios (HR) of overall survival (OS) of afatinib against gefitinib, erlotinib and PC strategy had substantial influential parameters. Conclusions First-line afatinib is cost-effective compared with gefitinib, erlotinib and PC treatment for Chinese patients with EGFR mutation-positive NSCLC. [ABSTRACT FROM AUTHOR]