Purpose The Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) study showed a 15.7-month survival benefit with the addition of pertuzumab (P) to docetaxel and trastuzumab (TH) as first-line treatment for patients with HER2 overexpressing metastatic breast cancer. We performed a cost-effectiveness analysis to assess the value of the addition of pertuzumab to docetaxel and trastuzumab. Patient and Methods We developed a decision-analytic Markov model to evaluate the cost-effectiveness of TH with or without P in U.S. patients with metastatic breast cancer. The model followed patients weekly over their remaining lifetimes. Health states included: stable disease, progressing disease, hospice, and death. Transition probabilities were based on the CLEOPATRA study. Costs reflected the 2014 Medicare rates. Health state utilities were the same as those used in other recent cost-effectiveness studies of trastuzumab and pertuzumab. Outcomes included health benefits expressed as discounted quality-adjusted life-years (QALYs), costs in U.S. dollars, and cost-effectiveness expressed as an incremental cost-effectiveness ratio. One-way and multi-way deterministic and probabilistic sensitivity analyses explored the effects of specific assumptions. Results Modeled median survival was 39.4 months (TH) and 56.9 months (THP). The addition of pertuzumab resulted in an additional 1.81 life years gained (0.62 QALYs) at a cost of $472,668 per QALY gained. Deterministic sensitivity analysis showed that THP is unlikely to be cost-effective even under the most favorable assumptions, and probabilistic sensitivity analysis predicted 0% chance of cost-effectiveness at a willingness-to-pay of $100,000 per QALY gained. Conclusion The addition of pertuzumab to docetaxel and trastuzumab in patients with metastatic HER2+ breast cancer is unlikely to be cost-effective in the United States. Citation Format: Qian Y, Durkee BY, Pollom EL, King M, Dudley SA, Shaffer JB, Chang DT, Gibbs IC, Goldhaber-Fiebert JD, Horst KC. Cost-effectiveness of pertuzumab in HER2+ metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-11-01.