Trastuzumab deruxtecan (T-DXd) - antibody - drug conjugate targeting the human epidermal growth factor receptor 2 (HER2) - has demonstrated high efficacy in clinical studies, with high rates of durable responses and improved outcomes in HER2-positive and HER2-low metastatic breast cancer (mBC) patients. T-DXd has demonstrated a generally manageable safety profile across the DESTINY trials, but there is an emerging unmet need for additional real-world clinical practice information. Italian experts conducted a Delphi panel and several roundtables to develop recommendations for the prevention and practical management of T-DXd-related AEs and toxicities, including nausea and vomiting (N/V), neutropenia, anemia, cardiovascular events, interstitial lung disease/pneumonitis (ILD/P), and treatment safety. ILD/P and N/V are the most challenging AEs associated with T-DXd. Being T-DXd now classified as a Highly Emetogenic Chemotherapy, Italian experts recommend pre-treatment with the triplet (NK1 RA + 5-HT3 RA + dexamethasone) in all patients to prevent acute N/V. Patients must be monitored early on treatment for signs/symptoms of ILD/P and any clinical suspicion should be promptly investigated and managed according to guidelines. These recommendations and proactive surveillance may substantially improve the management of T-DXd-related AEs, maximizing the benefit of this treatment for HER2-positive and HER2-low mBC, and potentially increasing treatment acceptance.