To evaluate the cost-effectiveness of Afatinib compared to Gefitinib and Erlotinib in the treatment of non-small cell lung cancer with EGFR mutations in Vietnam. Methods: A model-based cost-effectiveness analysis was conducted which employed the payer's perspective. The partition survival modeling (PSM) was used to simulate the survival time of the non-progressive disease and the overall survival time of the study patient population, with a time horizon of 10 years and a cycle length of 1 month. Treatment cost parameters and adverse event management are collected based on clinical expert consultation. Parameters of clinical efficacy and quality of life are collected from published sources. Results: The treatment regimen with Afatinib had a higher total cost than Gefitinib and Erlotinib, and the number of life years gained and QALY gained was also higher than that of Gefitinib and Erlotinib. The ICER index is VND 178,694,204 and VND 190,963,102 for each additional QALY. Conclusion: The treatment of non-small cell lung cancer with EGFR mutation in Vietnam with Afatinib is cost-effective when compared to Gefitinib and Erlotinib.