OBJECTIVES:: The Chilean national health service does not have an official recommendation regarding the initiation of pharmacological treatment in patients with Chronic Myeloid Leukemia (CML). First and second-generation tyrosine kinase inhibitors (ITKs) are used indistinctly with a high associated cost for the public health care system. The aim of this study is to establish the most cost-effective option in these patients. METHODS:: Markov models were designed based on information obtained from clinical trials. Initial treatments of CML with Imatinib (400 mg once daily), dasatinib (100 mg once daily) and nilotinib (300 mg twice daily) were compared. Costs from the hospital paying perspective and direct medical costs were considered. Willingness to pay was defined as three times the Chilean per capita GDP (CLP $10.226.000 in 2013). Probabilistic and deterministic simulations and sensitivity analyses were performed. RESULTS:: Neither of the second-generation drugs (dasatinib and nilotinib) were cost-effective compared to the first generation drug (imatinib) at time horizons of both 5 and 10 years. The incremental cost-effectiveness ratio (ICER) at 10 years in the deterministic simulation was CLP $370,770,321 / QALY (dasatinib versus imatinib) and CLP $85,543,684 / QALY (nilotinib versus imatinib). Both options are clearly dominated by the first generation drug. CONCLUSIONS:: Both dasatinib and nilotinib are not cost-effective compared to imatinib in 5 and 10 years simulations. We suggest that second-line drugs be reserved for when the patient does not respond appropriately to the first generation drug.