This study was undertaken to determine the value of angiogenesis and blood vessel invasion (BVI) using both Factor VIII-related antigen and elastica van Gieson staining in predicting 20-year relapse-free survival (RFS) and 20-year overall survival (OS) rates in Japanese patients with node-negative breast cancer. Two hundred and sixty patients were studied. We investigated nine factors, including angiogenesis (average microvessel count (AMC)), BVI, proliferating cell nuclear antigen (PCNA), p53, c-erbB-2, clinical tumor size (T), histological grade, tumor necrosis, and lymphatic vessel invasion (LVI). Twenty-five patients (9.6%) had recurrence and 17 patients (6.5%) died of breast cancer. Univariate analysis showed that BVI, AMC, T, histological grade, PCNA, p53, and tumor necrosis were significantly predictive of RFS or OS. Multivariate analysis showed that AMC, BVI, and T were significant independent factors for RFS or OS. Moreover, the combination of AMC/BVI was an especially significant factor for RFS or OS (P < 0.0001, P = 0.0003, respectively). When stratified by T, a significant impact of AMC or BVI on RFS was seen in patients with T1, T2, and T3 carcinomas. Multivariate analysis in patients with T2 carcinoma showed that both AMC and BVI were significant independent factors for RFS (P = 0.0231, P = 0.0388, respectively) and OS (P = 0.0331 and P = 0.0479, respectively). AMC, BVI, and T were independent prognostic indicators. As the combined impact of AMC/BVI is especially strong, AMC/BVI is useful in selecting high-risk node-negative breast cancer patients who may be eligible to receive aggressive adjuvant chemotherapy.