Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADCs) with high extracranial activity in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC). In this breast cancer subtype, brain metastases (BM) are a common and devastating complication. While intracranial activity of small-molecule tyrosine kinase inhibitors is well established, the potential role of larger molecules such as ADCs remains ill-defined. The single-centre, single-arm, phase 2 trial TUXEDO-1 trial therefore enrolled patients with HER2-positive mBC and active (i.e., newly diagnosed or progressive) BM; intracranial response rate was defined as the primary study endpoint. In the intention-to-treat population, best intracranial response rate was 73.3% (95% confidential interval 48.1-89.1%), thus suggesting comparable extra- and intracranial activity. T-DXd should therefore be considered as a treatment option in the setting of HER2-positive breast cancer.