PURPOSE: The most important independent prognostic factors of breast cancer have been reported to the tumor size and lymph node metastasis, as well as DNA ploidy, proliferation index, and various receptors, including estrogen receptor (ER) and progesteron receptor (PR) and oncogenes, such as c-erbB-2, and the tumor suppressor gene, p53. However, all these prognostic factors are still unable to exactly estimate distant metastasis for breast cancer. Based on this, our aim was to study for the prognostic factors that associated distant metastasis of breast cancer with cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF), which are related to angiogenesis, and Cyclin D1, which participates in cell proliferation in breast cancer. METHODS: A retrospective study was carried out on 95 patients, who has undergone an operation for breast cancer, with or without metastasis between January 1993 and July 2001, at the Department of Surgery, Chungnam National University Hospital. The study was based on the immunohistochemical staining of primary tumors for COX-2, VEGF, Cyclin D1, ER, PR and c-erbB-2, which were obtained from tissue samples of 45 and 50 patients with and with no distant metastatic breast cancer. SPSS for Windows, Version 10.0 was used for the statistical analyses. RESULTS: The expressions of COX-2, VEGF and Cyclin D1 were statistically significant in distant metastatic breast cancer. The clinicopathological parameters associated with distant metastasis were the tumor size and histological grade, and lymph node metastasis, lymphovascular invasion, ER and PR. There were positive correlations between 1) COX-2 and VEGF, 2) COX-2 and Cyclin D1, 3) c-erbB-2 and Cyclin D1 and 4) VEGF and Cyclin D1, COX-2 also had positive relationships with the tumor size and c-erbB-2, VEGF had positive relationships with lymph node metastasis, histological grade and lymphovascular invasion, as well as with ER and PR. The overexpressions of COX-2, VEGF and Cyclin D1 shortened the disease-free survival and survival period. CONCLUSION: The overexpressions of COX-2, VEGF and Cyclin D1 were considered poor prognostic factors for the induction of distant metastasis. Therefore, COX-2, VEGF and Cyclin D1 could be used in the prevention of distant metastasis, and prescribed for the treatment of metastatic breast cancer.