As part of its single technology appraisal process, the National Institute for Health and Care Excellence invited the manufacturer of pertuzumab (Perjeta®; Roche Products Limited) to submit evidence of its clinical and cost- effectiveness for the neoadjuvant treatment of women with high-risk, early-stage, HER2-positive breast cancer when used in combination with trastuzumab and chemotherapy. High-risk women included those with locally advanced (including inflammatory) breast cancer and women with high-risk early-stage breast cancer (classified as T2/3 or N1). The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group. This article presents the critical review of the company's submission by the Evidence Review Group and the outcome of the National Institute for Health and Care Excellence guidance. The clinical data were mainly taken from a phase II, randomised, open-label, active controlled study (NeoSphere), which reported a significant advantage in terms of pathological complete response rates of pertuzumab in combination with trastuzumab and chemotherapy, compared with trastuzumab alone with chemotherapy (45.8 vs. 29.0%, p = 0.0141). The company did not make any indirect comparisons. A meta-analysis of 12 neoadjuvant studies investigating the relationship between pathological complete response and event-free survival was used to extrapolate the outcomes reported in the NeoSphere study. A cardiac safety study (TRYPHAENA) demonstrated the safety of pertuzumab. The company undertook a model-based economic evaluation of neoadjuvant pertuzumab plus trastuzumab and docetaxel compared with neoadjuvant trastuzumab and docetaxel over a lifetime horizon from the National Health Service and Personal Social Services perspective. The probabilistic incremental cost-effectiveness ratio was estimated to be £20,104 per quality-adjusted life-year gained for pertuzumab alongside trastuzumab and docetaxel compared with trastuzumab and docetaxel, which was revised to £21,869 per quality-adjusted life-year gained following the clarification process. The Evidence Review Group corrected an error in the digitisation of the survivor functions and modified the clinically inappropriate assumption that recurrence is zero after 7 years. The Evidence Review Group's probabilistic base case was £23,962 per quality-adjusted life-year gained. During the appraisal, to mitigate the uncertainties associated with the evidence, the company offered a patient access scheme, which led to the National Institute for Health and Care Excellence Appraisal Committee recommending pertuzumab in this patient group, subject to the company providing the agreed discount in the patient access scheme.