The angiogenic factor vascular endothelial growth factor (VEGF) predicts outcome in primary breast carcinoma. Alteration of the p53 gene causes down‐regulation of the expression of thrombospondin‐1, a natural inhibitor of angiogenesis. This study was conducted to investigate the association between mutant p53 protein and VEGF expression, and the prognostic value of these factors. VEGF₁₆₅ and p53 protein were measured in tumour cytosols by enzyme immunoassays. Recurrence‐free survival (RFS) and overall survival (OS) were estimated in 833 consecutive patients, 485 node‐negative (NNBC) and 348 node‐positive (NPBC) with primary invasive breast cancer. A significant association was found between mutant p53 protein and VEGF expression. Univariate analysis showed both p53 and VEGF to be significant predictors of survival. Similar correlation was seen when p53 was combined with VEGF. Univariate analysis of NNBC showed significant prognostic value of p53 for OS, also when combined with VEGF expression; for NPBC, significant reductions in RFS and OS were seen for p53‐positive patients, and these findings were enhanced when combined with VEGF, also in the sub‐group receiving adjuvant endocrine treatment. Multivariate analysis showed both p53 and VEGF as independent predictors of OS in all groups. When the 2 factors were combined, an increased relative risk of 2.7 was seen for OS in the group with both p53 positivity and high VEGF content, as compared with 1.7 in the group with one risk factor. The results suggest an association between loss of wt‐p53 and increased VEGF expression, indicating that angiogenic activity may depend, at least partly, on altered p53‐protein function. Combination of these 2 biological markers appears to give additional predictive information of survival. A high‐risk group of patients was associated with p53 positivity and higher VEGF content. Int. J. Cancer (Pred. Oncol.) 89:51–62, 2000. © 2000 Wiley‐Liss, Inc.