Background: In the last decades, the proportion of breast cancer patients receiving breast-conserving surgery has increased, reaching 70-80% in developed countries. In case of non-palpable lesions, surgical excision requires some form of breast localization. While wire-guided localization has long been considered gold standard, it carries several limitations, including logistical difficulties, the potential for displacement and patient discomfort, and re-excision rates reaching 21%. Other techniques (radioactive seed or radio-occult lesion localization, intraoperative ultrasound, magnetic, radiofrequency and radar localization) have been developed with the aim of overcoming these disadvantages. However, comparative data on the rates of successful lesion removal, negative margins and re-operations are limited. In the majority of studies, the patient’s perspective with regard to discomfort and pain level has not been evaluated. The aim of MELODY is to evaluate different imaging-guided localization methods with regard to oncological safety, patient-reported outcomes, and surgeon and radiologist satisfaction. Methods: The EUBREAST and the iBRA-NET have initiated the MELODY study to assess breast localization techniques and devices from several perspectives (NCT05559411, http://melody.eubreast.com). MELODY is a prospective intergroup cohort study which enrolls female and male pts. requiring breast-conserving surgery and imaging-guided localization for invasive breast cancer or DCIS. Multiple or bilateral lesions and neoadjuvant chemotherapy are allowed. Primary outcomes are: 1) Intended target lesion and/or marker removal, independent of margin status on final histopathology, and 2) Negative resection margin rates at first surgery. Secondary outcomes are, among others: rates of second surgery and secondary mastectomy, Resection Ratio (defined as actual resection volume divided by the calculated optimum specimen volume), duration of surgery, marker dislocation rates, rates of marker placement or localization failure, comparison of patient-reported outcomes, rates of “lost markers” and diagnostician/radiologist’s and surgeon’s satisfaction as well as the health economic evaluation of the different techniques. Target accrual: 7,416 patients. Enrollment started in January 2023. The study will be conducted in 20 countries and is supported by the Oncoplastic Breast Consortium (OPBC), AWOgyn, AGO-B and SENATURK. Clinical trial information: NCT05559411.