OBJECTIVES:  To compare the cost-utility of first-line gefitinib, erlotinib and afatinib in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)- mutations in the Netherlands. METHODS:  A Markov model was developed from the societal perspective, according to Dutch guidelines, to assess the cost-utility of gefitinib, erlotinib and afatinib. The model was based on data from the WJTOG3405, OPTIMAL and Lux-Lung 6 trials. The incremental cost-utility ratio (ICUR) per quality-adjusted life-year (QALY) gained and incremental cost-effectiveness ratio (ICER) per life-year (LY) gained were estimated. Univariate and probabilistic sensitivity analyses were conducted to test the robustness of the model and the uncertainty within parameters. RESULTS:  Base case analysis showed that the total discounted per patient costs for gefitinib, erlotinib and afatinib were €67,505, €59,322 and €69,037, respectively. QALYs gained for gefitinib, erlotinib and afatinib were 1.52, 1.31 and 1.61 per patient. LYs gained for gefitinib, erlotinib and afatinib were 2.79, 2.25 and 2.95, respectively. Gefitinib compared to erlotinib resulted an ICUR of €38,098/QALY and an ICER of €15,205/LY gained. Afatinib resulted in €17,924/QALY and €9,698/LY in comparison with gefitinib. Relative to erlotinib, afatinib showed an ICUR of €32,357/QALY and an ICER of €13,956/LY gained. Sensitivity analysis revealed that drug costs for all treatments were influential drivers. CONCLUSIONS:  At a threshold of €80,000/QALY, afatinib is a cost-effective treatment option in comparison with gefitinib and erlotinib. Hence afatinib is the most favorable drug for patients with NSCLC who harbor EGFR-mutations in the Netherlands.