The biological significance of occult metastases in axillary lymph nodes of breast cancer patients is controversial. The purpose of the study was to determine the prognostic significance of occult micrometastases using the current American Joint Committee on Cancer (AJCC) staging system in a cohort of women with node-negative breast cancer, of whom 5% received adjuvant systemic therapy and who all had long-term follow-up. We studied a cohort of 214 consecutive histologically node-negative breast cancer patients with a median follow-up of 8 years. Blocks of the axillary lymph nodes were assessed for occult micrometastases by examination of an additional hematoxylin-eosin-stained slide and by immunohistochemical staining using an antibody to low molecular weight keratin. Occult metastases were classified according to the sixth edition of the AJCC cancer staging manual. We examined the prognostic effects of occult micrometastases and other clinicopathologic features on recurrence outside the breast with disease-free interval (DFI) and survival from breast cancer with disease-specific survival (DSS). Cytokeratin-positive tumor cells were identified in the lymph nodes in 29 of 214 cases (14%). Two cases had isolated tumor cells and no cluster larger than 0.2 mm [pN0(i+)], whereas 27 of 214 (13%) had micrometastases (larger than 0.2 mm and <or=2.0 mm] (pN1mi). None of the cases had macrometastases. With median 8 years follow-up, occult micrometastases were not significantly associated with any of the clinicopathologic features. In addition, occult micrometastases were not significantly associated with DFI or DSS and thus were not included in the multivariate analysis. On multivariate analysis, lymphovascular invasion was significantly associated with DFI (p < 0.001) and DSS (p = 0.02), whereas percentage S-phase was significantly associated with DSS (p = 0.02). This study, in which 95% of patients did not receive adjuvant systemic therapy, suggests that breast cancer patients with occult micrometastases in axillary lymph nodes have a similar prognosis to those with no micrometastases. This information is important with regard to the practice of sentinel node biopsy and subsequent axillary node dissection and to the decision to administer adjuvant therapy based on detection of micrometastases in lymph nodes.