OBJECTIVES: Despite major advances, resistance and intolerance continue to be a significant challenge in the management of CML. This study evaluated the real-world resource use and costs associated with CML treatment failure with dasatinib or nilotinib (defined as treatment switch or discontinuation) from a US payer perspective.   METHODS: This was a retrospective study using the IMS PharMetrics health plan claims database from July 2006-June 2011. Adult patients with CML diagnosis (ICD-9 205.1x) with ≥1 fill of dasatinib or nilotinib were selected. Failure was defined as a switch to another tyrosine kinase inhibitor (TKI) or a gap in index TKI >90 days. Direct medical resource use and costs (2011 USD) were measured for those with 6 months of continuous enrollment post-failure, including all-cause medical and pharmacy costs. RESULTS: 608 CML patients were identified initiating dasatinib or nilotinib, of which 290 experienced treatment failure. Of these, 192 had 6 months of continuous enrollment post-failure. Average age was 57.5 years and 55.7% were female. Mean 6-month costs post-failure were $79,996 (median $33,100), with inpatient costs comprising 54.4%, followed by pharmacy (23.1%) and outpatient (22.2%). During the 6 months post-failure, one-third of patients had at least one hospitalization (median 12 days) with leukemia being the most frequent primary diagnosis for hospitalization, 22% had an emergency room visit, 96% had physician office visits (median 11 visits), with a median of 27 lab tests and 20 prescription fills per person (median 16 non-TKI fills). CONCLUSIONS: The 6-month economic burden of failure from nilotinib and dasatinib is substantial and is largely due to the disease. The availability of new agents to effectively manage this hard-to-treat population has the potential to improve costs of care by preventing disease progression.