OBJECTIVES: To evaluate the cost-effectiveness of afatinib, erlotinib, and cisplatin/pemetrexed chemotherapy, for first-line treatment of metastatic EGFR-mutation positive non-small cell lung cancer (NSCLC). METHODS: A Markov model simulated the lifetime progression of EGFR-mutation positive stage IIIB/IV NSCLC patients, under each treatment option, from a US societal perspective. Probabilities, survival rates and health utilities were obtained from clinical trials (LUX-3, LUX-6, EURTAC and OPTIMAL) and published literature. Progression-free and overall survival in the erlotinib trial were adjusted up to account for differences in poorer ECOG performance status compared to the afatinib trial. Costs included those for drugs, progression, and side effects in 2013 USD. Expected QALYS were calculated. The impact of varying parameters on model outcomes was examined using probabilistic sensitivity analyses. RESULTS: In the base-case model, treatment with afatinib was least expensive, with lifetime cost of $38,406, followed by cisplatin/pemetrexed ($40,714), and erlotinib ($41,344). Survival was highest with erlotinib (5.27 quality-adjusted life-months saved [QALMS]), followed by afatinib (4.02 QALMS), and cisplatin/pemetrexed (3.51 QALMS). Compared to erlotinib, afatinib had lower monthly drug costs ($5,648 versus $5,853), but higher overall side effects costs ($3,669 versus $1,690). Cisplatin/pemetrexed was dominated by afatinib. Erlotinib was cost-effective compared with afatinib (ICER=$28,210/QALYS). In a model without survival adjustments, afatinib compared with erlotinib had an ICER over the WTP threshold (ICER=$542,745/QALYS), with erlotinib remaining the cost-effective option. Afatinib becomes more cost-effective than erlotinib when its monthly drug cost decreased from $5,648 to below $3,802. CONCLUSIONS: Based on our analyses, we recommend erlotinib as the most cost-effective first-line treatment for EGFR-mutation positive NSCLC. Given the potentially similar relative efficacy between afatinib and erlotinib in the clinical trials, cost-effectiveness analysis of afatinib versus erlotinib depends mostly on differences in drug and side-effects costs. Thus, afatinib may need to earn its share of the NSCLC market space with more competitive pricing.