Despite significant advances in micro-metastasis detection methods, little is known about the relationship between micro-metastasis and primary tumors. The purpose of this study was to assess the ability of expression of the breast cancer-related markers, HER-2/neu, COX-2, VEGF and PDGF-B, as a predictor for micro-metastasis. As destination sites for micro-metastasis, we examined the peripheral blood (BD), bone marrow (BM) and sentinel lymph node (SLN) from 53 breast cancer patients. Protein and gene expression of the markers at the primary site were determined by immunohistochemistry (IHC) and quantitative RT-PCR. BD and BM samples were processed using magnetic-activated cell separation and immunocytochemistry. SLNs were examined by hematoxylin and eosin (H&E) staining and IHC. The percentages of patients with micro-metastasis were 24.5% in BD, 56.6% in BM, 26.4% in SLN by H&E and 41.5% in SLN by IHC. COX-2 gene amplification was significantly associated with SLN micro-metastasis by H&E (P=0.03). Overexpression of HER-2/neu predicts the presence of SLN micro-metastasis as detected by H&E (P=0.005) and COX-2 overexpression predicts the presence of micro-metastasis in BM (P=0.005) and SLN by H&E (P<0.001) and IHC (P<0.001). Similarly, PDGF-B overexpression predicts micro-metastasis in BD (P=0.002), BM (P=0.003) and SLN by H&E (P=0.017), whereas VEGF overexpression predicts only the presence of SLN micro-metastasis by IHC (P=0.001). Our results indicate the possible value of using these markers to predict the risk of micro-metastasis in breast cancer.