Background and Purpose: In recent years, the treatment landscape for breast cancer has undergone signif-icant advancements, with the introduction of several new anticancer agents. One such agent is trastuzu-mab emtansine (T-DM1), an antibody drug conjugate that has shown improved outcomes in both early and advanced breast cancer. However, there is currently a lack of comprehensive evidence regarding the safety profile of combining T-DM1 with radiation therapy (RT). In this study, we aim to provide a summary of the available data on the safety of combining RT with T-DM1 in both early and metastatic breast cancer settings.Materials and Methods: This systematic review and meta-analysis project is part of the consensus recom-mendations by the European Society for Radiotherapy and Oncology (ESTRO) Guidelines Committee on integrating RT with targeted treatments for breast cancer. A thorough literature search was conducted using the PUBMED/MedLine, Embase, and Cochrane databases to identify original studies focusing on the safety profile of combining T-DM1 with RT.Results: After applying eligibility criteria, nine articles were included in the meta-analysis. Pooled data from these studies revealed a high incidence of grade 3 + radionecrosis (17%), while the rates of grade 3 + radiation-related pneumonitis (<1%) and skin toxicity (1%) were found to be very low.Conclusion: Although there is some concern regarding a slight increase in pneumonitis when combining T-DM1 with postoperative RT, the safety profile of this combination was deemed acceptable for locore-gional treatment in non-metastatic breast cancer. However, caution is advised when irradiating intracra-nial sites concurrently with T-DM1. There is a pressing need for international consensus guidelines regarding the safety considerations of combining T-DM1 and RT for breast cancer.& COPY; 2023 The Author(s). Published by Elsevier B.V. Radiotherapy and Oncology 186 (2023)109805 This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).