The prognostic value of the determination of peritumoral vessel invasion (PVI) in node-negative breast cancer (NNBC) patients is still controversial. This is mainly related to the subjective criteria of evaluation of this histologic finding using morphological methods only. In this study, to assess PVI by stricter criteria, we used both conventional morphological and immunocytochemical techniques, using antibodies specific to endothelial cells (i.e. factor VIII-related antigen and the CD-31 antibody). In a series of 233 evaluable NNBC, with a median follow-up of 5 years, we found that 11% of the tumors (25 out of 233) were PVI-positive. A weak association was observed only between PVI and tumor size (p = 0.076). In univariate analysis PVI significantly predicted relapse-free survival (p = 0.0009), but not overall survival (p = 0.1208). The odds of relapse and death for patients with PVI-positive carcinomas were 4.36 and 2.24 times higher than for those with PVI-negative tumors. As far as relapse-free survival is concerned, tumor size (p = 0.0012), histologic grading (p = 0.022), estrogen receptor (p = 0.016) and progesterone receptor expression (p = 0.017) also had a significant prognostic value. Only tumor size significantly predicted overall survival (p = 0.0038) in this series. For 5-year relapse-free survival both PVI (p = 0.014) and tumor size (p = 0.017) were significant and independent prognostic variables by multivariate analysis. Our results demonstrate that PVI and tumor size are important histological features to identify high-risk NNBC patients. Further studies are needed to compare the prognostic significance of PVI and tumor size with that of novel biological prognostic indicators of emerging importance in this neoplasia.