OBJECTIVES: Erlotinib, the first generation of epidermoid growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), has been recommended as an essential treatment in EGFR mutation non-small-cell lung cancer (NSCLC) patients with significant progression free survivals (PFS). However, the overall survival (OS) benefit was limit resulting in a request of financial consideration of this strategy. Based on the current cost-effectiveness analysis, a new financial insight into erlotinib mono-treatment compared with gemcitabine-included doublet chemotherapy in the first-line treatment of EGFR mutation Asian NSCLC patients would be provided. METHODS: According to the two phase III, randomized, open-label ENSURE trial (NCT01342965) and OPTIMAL trial (CTONG-0802), two groups (Erlotinib arm and Chemotherapy arm) and three health states (PFS, progressive disease (PD) and death) were analyzed in our Markov model. All the medical costs were calculated from a Chinese health care system. Quality-adjusted life year (QALY) and incremental cost-effectiveness ratios (ICERs) were applied as the primary outcomes. RESULTS: The combined PFS were 11.81 months and 5.1months for erlotinib and chemotherapy respectively, while the OS were much closer, 24.68 months for erlotinib and 26.16 months for chemotherapy. Chemotherapy arm gained a 0.13 QALYs compared with erlotinib monotherapy(1.17 QALYs VS. 1.04 QALYs), while a lower cost was found in erlotinib arm ($55,230.34 versus $77668.54), resulting in an ICER of $174,808.0 per QALY for chemotherapy arm($53,244.35 per QALY in Erlotinib arm; $ 66,630.61 per QALY in Chemotherapy arm), which exceeded the willingness to pay. Health utility of PD and PFS state as well as the subsequent treatments cost of chemotherapy arm were the most influential factors in the robustness of the model.  CONCLUSIONS: Erlotinib monotherapy may be acceptable as a more cost-effective first-line treatment for NSCLC compared with gemcitabine based chemotherapy. The patients’ health status and subsequent treatments played key roles in determining which strategy was more cost-effective.