To assess the prognostic significance of peritumoral vessel invasion, data were examined for 1,510 women entered into the Ludwig Breast Cancer Group Trials I to IV evaluating adjuvant therapy for operable breast cancer with axillary nodal metastasis. Vessel invasion by tumor cells was identified by routine light microscopy in 59 per cent (889 of 1,510) of the patients and was equally distributed between premenopausal/perimenopausal (60 per cent, 468 of 778) and postmenopausal (58 per cent, 421 of 732) women. In logrank analyses stratified by nodal status (one to three or four or more positive nodes), the four-year disease-free survival (DFS) rate was significantly lower in patients with vessel invasion than in women without vessel invasion (50 per cent versus 65 per cent, P less than 0.0001). This DFS difference was seen for both premenopausal/perimenopausal (P = 0.0004) and postmenopausal (P = 0.0002) patients. The four-year overall survival rate was also lower in patients with vessel invasion (71 per cent versus 82 per cent, P = 0.0006), both for premenopausal/perimenopausal (P = 0.002) and postmenopausal (P = 0.04) women. The presence of vessel invasion was significantly associated with increasing numbers of positive axillary lymph nodes, rising tumor grade, nonstellate tumor border growth pattern, and higher steroid hormone receptor content of the primary tumor. The assessment of peritumoral vessel invasion continued to have prognostic significance for DFS (P less than 0.0001) and overall survival (P = 0.003) when evaluated in multivariate models controlling for treatment assigned, nodal status, tumor size, estrogen receptor status, menopausal status, and age. Depending on the subpopulation, patients with vessel invasion had a 41 per cent to 54 per cent greater risk of treatment failure than those without vessel invasion and a 29 per cent to 64 per cent greater risk of death. The percentage of treatment failures at distant sites was higher for women with than for those without vessel invasion (27 per cent versus 18 per cent, P = 0.003). In patients with axillary lymph node metastases, peritumoral vessel invasion may be a sign of increased systemic disease burden.