Objectives To investigate the association of circulating E-cadherin (E-cad) and epidermal growth factor receptor (EGFR) with pathological behavior of breast cancer. Methods Totally 49 patients diagnosed with triple negative breast cancer (TNBC group),198 patients diagnosed with non-triple negative breast cancer (NTNBC group) and 50 healthy subjects were involved in this study. Concentration of E-Cad and EGFR were obtained by enzyme-linked immunosorbent assay (ELISA) and the expression of FOXA1 was measured by immunohistochemistry. The clinical diagnostic value of serum E-cad and EGFR in breast cancer or TNBC was evaluated by ROC curve. The Youden index was utilized to evaluate the diagnostic threshold of E-cad and EGFR. Results Expression levels of E-Cad, EGFR and FOXA1 in breast cancer patients were significantly increased (P < 0.01) compared with healthy volunteers. No statistically significant difference in E-Cad was observed between TNBC group and NTNBC group (P > 0.05). Concentration of EGFR increased (P < 0.01) while FOXA1 decreased (P < 0.01) significantly in TNBC group when compared with NTNBC group. ROC curve showed that AUC of E-Cad and EGFR for breast cancer was 0.965 (95% CI: 0.944, 0.986) and 0.758 (95% CI: 0.686, 0.830), respectively. At the threshold of 1 010.7 ng/ml for E-Cad and 107.9 ng/ml EGFR, the Youden index was 0.807 and 0.385, sensitivity for diagnosis of breast cancer was 92.7% and 78.5%, and the specificity was 88.0% and 60%, respectively. AUC of EGFR for diagnosis of TNBC was 0.776 (95% CI: 0.703, 0.848). At the threshold of 139.5 ng/ml, the largest Youden index was 0.473, the sensitivity was 79.6%, and the specificity was 67.7%. Conclusion E-cad and EGFR can be used as indicators of diagnosis for breast cancer while FOXA1 and EGFR can be a diagnostic candidate for diagnosis of TNBC.