Background: Women with early breast cancer that has spread to 1 or 2 sentinel nodes (SNs) undergo axillary node clearance (ANC) or axillary radiotherapy (ART). The publication of the Z11 trial challenged this practice. There are however concerns about this trial which may limit the interpretation and generalisability of its results. These issues include the proportion of patients with micrometastases, variability in radiotherapy and applicability in patients undergoing mastectomy. Therefore further randomized trials are needed to define the role of axillary treatment in patients with 1 or 2 SNs with macrometastases. The UK-ANZ POSNOC trial is asking this question and will provide a more solid evidence base to inform clinical practice. Methods: Trial design: A pragmatic, randomized, multicenter, non-inferiority trial. Interventions:All participants will receive systemic adjuvant therapy according to local guidelines and radiotherapy to breast or chest wall if indicated. Women in the intervention group will receive systemic adjuvant therapy alone, whereas those receiving standard care will receive adjuvant therapy plus ANC or ART. Study population: Women with unifocal or multifocal invasive breast cancer( ≤ 5 cm) undergoing breast conserving surgery or mastectomy, node-negative by clinical and ultrasound examination, who have 1 or 2 nodes with macrometastases at SN biopsy and no extranodal extension. The sample size is 1900 women. All participants will be followed up for 5 years. Primary outcome: axillary recurrence at 5 years. Secondary outcomes: arm morbidity, quality of life, anxiety, loco-regional recurrence, distant metastasis; time to axillary recurrence, axillary recurrence-free survival, disease-free and overall survival, contralateral breast cancer, non-breast malignancy and economic evaluation. Key differences from Z11: a) stringent radiotherapy quality assurance program, b) prospective pathology reporting, b) axillary ultrasound is mandatory, b) mastectomy patients are eligible, c) axillary treatment in the standard group may be ANC or ART. Current enrollment: 35 patients. Clinical trial information: ISRCTN54765244.