The National Institute for Health and Care Excellence (NICE) provides guidance to improve health and social care in England and Wales. NICE invited Daiichi Sankyo to submit evidence for the use of trastuzumab deruxtecan (T-DXd) for treating human epidermal growth factor 2 (HER2)-positive unresectable or metastatic breast cancer (UBC/MBC) after two or more anti-HER2 therapies, in accordance with NICE’s Single Technology Appraisal process. The Liverpool Reviews and Implementation Group, part of the University of Liverpool, was commissioned to act as the Evidence Review Group (ERG). This article summarises the ERG’s review of the evidence submitted by the company and provides an overview of the NICE Appraisal Committee’s (AC’s) final decision made in May 2021. Results from the company’s base-case fully incremental analysis showed that, compared with T-DXd, eribulin and vinorelbine were dominated and the incremental cost-effectiveness ratio (ICER) per quality-adjusted life year (QALY) gained versus capecitabine was £47,230. The ERG scenario analyses generated a range of ICERs, with the highest being a scenario relating to a comparison of T-DXd versus capecitabine (£78,142 per QALY gained). The ERG considered that due to a lack of appropriate clinical effectiveness evidence, the relative effectiveness of T-DXd versus any comparator treatment could not be determined with any degree of certainty. The NICE AC agreed that the modelling of overall survival was highly uncertain and concluded that treatment with T-DXd could not be recommended for routine use within the National Health Service (NHS). T-DXd was, however, recommended for use within the Cancer Drugs Fund, provided Managed Access Agreement conditions were followed.