OBJECTIVES: In CP-CML, there are few therapeutic options for highly-resistant patients (e.g. third line [3L] or beyond), who have a poor prognosis. Current treatment options are tyrosine kinase inhibitors (TKIs) and allogeneic stem cell transplantation (allo-SCT) for suitable patients. Efficacy of ponatinib, designed to inhibit the kinase activity of native BCR-ABL and all mutant variants, including T315I, was demonstrated in patients with highly-resistant CML in the pivotal phase II Ponatinib Ph+ ALL and CML Evaluation(PACE) trial. In the absence of head-to-head trials, an economic model employing a Swedish public healthcare perspective was developed to assess the cost-effectiveness of ponatinib for 3L treatment of CP-CML compared with current treatment options in Sweden. METHODS: The cost-effectiveness model compares ponatinib, second-generation TKIs (dasatinib, nilotinib, bosutinib), and allo-SCT, with cost per life-years (LY) saved and cost per quality-adjusted life-years (QALYs) gained as outcome measures, and a lifetime time horizon. Resource use includes study drugs, monitoring and follow-up, adverse events and allo-SCT procedure. Costs, based on current tariffs in Sweden, and benefits (LY and QALYs) projected based on 12-month treatment response, were discounted at 3%/year. We performed sensitivity analyses (SA) to identify parameters that most strongly influenced results. Clinical validity was evaluated by comparing model-generated survival estimates with relevant clinical data. RESULTS: Over the patients’ lifetime, ponatinib provides an increase in LY of almost 7 years and a gain of almost 4 QALYs compared with the next-best therapy, bosutinib. The incremental cost-effectiveness ratios range from SEK78,044/QALY gained vs. allo-SCT to SEK351,702/QALY gained vs. bosutinib. SA showed the model was robust to plausible changes in input parameters and had good face validity. CONCLUSIONS: This analysis suggests that treating 3L CP-CML with ponatinib provides substantial clinical benefit as compared with current alternatives at a reasonable cost, from the perspective of the Swedish public healthcare system.