OBJECTIVES: To calculate the distribution among treatment related average costs of the use of TKI’s versus the combination of pemetrexed/cisplatin in relation to four core cost items: Acquisition, application, medical care and disease progression. METHODS: A discrete event simulation cost-effectiveness model with one month cycles (progression free, disease progression and death) assessed treatment related costs in a five year horizon until death. Average costs for TKIs where taken from three different therapies: afatinib, erlotinib and gefitinib. Public institutional direct medical costs (2014 purchases and price tabulators) were retrieved to adopt the national health system perspective. Efficacy inputs where obtained from a network meta-analysis. Information gaps related to the use and frequency of medical resources where fulfilled with the results of a Delphi panel (10 oncologists of all major public institutions).  The distribution among core cost items was calculated and later compared to obtain its share from the total treatment cost. RESULTS: In the studied time horizon, the highest cost of treatment was reported by pemetrexed/cisplatin with US$175,563, followed by a TKI mean of US$124,005. Disease progression cost was the most expensive item among alternatives, with US$154,025 and a mean of US$85,240.88 for pemetrexed/cisplatin and the TKIs respectively. Cost distribution among acquisition, application, medical care and disease progression cost for the TKIs average was 19%, 0%, 12% and 69% respectively. Pemetrexed/cisplatin cost distribution was 5%, 2%, 5% and 88% at the same core items. CONCLUSIONS: The economic burden in the treatment of NSCLC with EGFR mutation is heavily weighted in the disease progression cost. Even though pemetrexed/cisplatin has the lowest drug acquisition cost, it has the most expensive cost of treatment as a whole. A drug acquisition investment in TKIs is worth paying as its cost of treatment was estimated to be lower in a five year horizon.