Background: Treatment failure due to TKI resistance or intolerance is a significant challenge in managing CML; however, there are limited data quantifying the associated real-world health care utilization and cost burden. Methods: Treatment episodes for adult patients with a CML diagnosis (ICD-9-CM 205.1x) initiating a TKI of interest (index TKI) during 6/2008-12/2011 were identified from the IMS PharMetrics Plus Health Plan Claims Database. Inclusion required 120-days pre- and 360-days post-index continuous enrollment and no clinical trial participation. A patient could contribute ≥1 episode. Treatment failure was defined as switch to a non-index TKI or discontinuation of index TKI (gap of ≥60 days) observed over 1 year post index. Episodes with failure were matched to those without, based on propensity scores generated by logistic regression including baseline demographic and clinical characteristics, index TKI, and therapy line. Mean all-cause 1-year post-index health care utilization and costs (in 2012 USD) per episode were compared between matched episodes. Results: Of 1,774 eligible episodes from 1,624 CML patients (mean age=52.9, 47.8% female), 547 Failure episodes (Fs) were matched to 547 Non-Failure episodes (NFs). As expected, compared to Fs, NFs had more TKI fills (F: 7.1; NF: 11.2; p<.05) over the 1 year post index. However, Fs had significantly higher % hospitalized (28.9% v 13.9%), more inpatient days (22.2 v. 8.5), more outpatient visits (24.1 v. 17.8) and more non-TKI prescription fills (34.0 v. 28.7) (all p<.05). Overall, Fs incurred lower pharmacy costs ($51,238 v. $72,450), but higher medical costs ($52,618 v. $18,180, including $31,305 v. $5,287 for hospitalization), and higher total costs ($103,857 v. $90,630) than NFs (all p<.05). A sensitivity analysis excluding 18 episodes (17 Fs, 1NF) with bone marrow or stem cell transplant yielded qualitatively similar results. Conclusions: Although TKI failures have lower pharmacy burden, their overall economic burden is higher, primarily due to increased inpatient days. These findings suggest that minimizing TKI failure through more efficacious treatment may decrease the overall health care burden and costs of managing CML.