It is still controversial whether the identification of micrometastases and isolated tumor cells in the axillary lymph nodes of patients with breast cancer has any prognostic value. We evaluated the prognostic role of isolated tumor cells and micrometastases in the axillary lymph nodes in 3,158 consecutive patients pT1-2 pN0-N1mi (with a single involved lymph node) and M0, referred to the Division of Medical Oncology after surgery performed at the European Institute of Oncology from April 1997 to December 2002. Median follow-up was 6.3 years (range 0.1-11 years). Sentinel lymph node biopsy (SLNB) and axillary lymph node dissection (ALND) were performed in 2,087 and 1,071 patients, respectively. A worse metastasis-free survival was observed for patients with micrometastatic disease compared to node-negative patients, if staged with ALND (log-rank P < .0001; HR: 3.17; 95% CI 1.72-5.83 at multivariate analysis), but not for patients who underwent SLNB (log-rank P = 0.36). The presence of a single micrometastatic lymph node is associated with a higher risk of distant recurrence as compared to node-negative disease only for patients undergoing ALND for staging purposes. Treatment recommendations for systemic therapy should not take into account the presence of a single micrometastatic lymph node identified during complete serial sectioning of sentinel node(s).