OBJECTIVES: To compare the economic impact from US societal perspective of Nilotinib and Dasatinib as second-line therapies in treatment of CML patients with Imatinib resistance or intolerance by conducting a cost-effectiveness analysis. METHODS: A Markov simulation model was developed to estimate quality adjusted life years (QALYs) and expected costs using data from head-to-head comparative clinical trials. Costs in the model included medication cost, hospitalization cost, physician fee, laboratory test fee, adverse events cost, and value of waiting time and were obtained from published literature and government and organization websites. All costs were adjusted to 2011 US dollars. The treatment pattern was assumed to be 800mg/day for Nilotinib, or 100mg/day for Dasatinib in the chronic phase and 140mg/day in the advanced phase.  Treatment was evaluated up to progression of the disease, best supportive care and up to death, operating 80 cycles of 3 months. Switching from one product to the other due to severe adverse events was also considered. Sensitivity analyses were performed to test the robustness of the results. RESULTS: In the base case analysis, the total cost for treatment with Nilotinib was $150,966, and Dasatinib was $126,672. Patients treated with Nilotinib gained 0.57 more life years, or 0.49 more QALYs, compared with Dasatinib. The incremental cost-effectiveness ratio (ICER) for Nilotinib therapy was $49,467/QALY, which indicated that Nilotinib is an advantageous treatment for CML patients in regards to treatment efficacy and cost effectiveness. One-way sensitivity analyses indicated the results to be robust. CONCLUSIONS: Based on a willingness-to-pay threshold of $120-$150,000/QALY, Nilotinib treatment in CML patients who were resistant or intolerant to Imatinib is a cost-effective treatment. The results, however, may be less applicable to high-risk patients, the elderly, children and those eligible for bone marrow transplantation.