BACKGROUND: In 1 of 3 patients with initial lymph node-positive (cN) breast cancer, neoadjuvant chemotherapy (NAC) results in an axillary pathologic complete response (ax-pCR). This urges the need for a less-invasive axillary staging method. Recently introduced less-invasive procedures have been insufficient in accurately identifying ax-pCR. Therefore, we propose a novel less-invasive axillary staging procedure: the Radioactive Iodine Seed localization in the Axilla with the Sentinel node procedure (RISAS), a combination of the procedure of marking axillary lymph nodes with radioactive iodine seeds (MARI) and sentinel lymph node biopsy (SLNB). PATIENTS AND METHODS: In the present open single-arm multicenter validation study, 225 cN (biopsy-proven) patients will undergo the RISAS procedure, in which a positive lymph node is marked by an iodine-125 seed before NAC. After NAC completion, this iodine-125 seed-marked lymph node is removed, together with any additional sentinel lymph nodes. The RISAS procedure is subsequently followed by completion axillary lymph node dissection (ALND). The RISAS lymph nodes will be compared with the lymph nodes from the completion ALND specimen. The primary endpoint is accuracy of the RISAS procedure. The identification rate, false-negative rate, negative predictive value, and possible concordance between the MARI and SLNB will be reported. CONCLUSION: The present prospective multicenter RISAS trial will enable us to validate the combination of MARI and SLNB for assessing the axillary response to NAC in cN patients. If RISAS proves to be an accurate axillary staging procedure, ALND could safely be abandoned in the case of ax-pCR confirmed using the RISAS procedure.