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The aim of this study was to investigate the cost-effectiveness of osimertinib for the treatment of advanced NSCLC with an EGFR T790M mutation after the failure of first-line EGFR tyrosine kinase inhibitor (TKI) therapy.A mathematical model was established by combining a decision tree and the Markov approach to project the cost-effectiveness of osimertinib versus standard chemotherapy for the treatment of patients who harbor an EGFR T790M mutation and have disease progression after first-line EGFR TKI therapy with or without metastases to the central nervous system. The clinical and outcome data were derived from randomized clinical trials and published reports. The health outcome data included quality-adjusted life-years (QALY). The cost data were estimated from the perspectives of the payer in the United States and the health care system in the People's Republic of China. All costs and incremental cost-effectiveness ratios (ICERs) were presented in 2017 U.S. dollars. Sensitivity and scenario analyses with three different settings of T790M mutation testing were performed.Compared with chemotherapy, molecular testing in plasma and tissue followed by osimertinib treatment yielded an additional 0.359 and 0.313 QALYs in the entire U.S. population and the population of those with central nervous system metastases and an EGFR T790M mutation. For these populations, the incremental costs were $83,515 and $74,924 per patient, respectively, and the ICERs were $232,895 and $239,274 per QALY, respectively. For the entire Chinese population and the Chinese population with central nervous system metastases, the ICERs were $48,081 and $53,244 per QALY, respectively. For those with a known T790M mutation, the ICERs of osimertinib over chemotherapy also exceeded the willingness-to-pay threshold. The most influential parameter was the price of osimertinib.Osimertinib treatment for T790M mutation NSCLC is unlikely to be cost-effective from the perspectives of the United States and the People's Republic of China. If the price of osimertinib could be decreased, the economic outcome might become favorable.