Primary squamous cell carcinoma of the breast (PSCCB) is an extremely rare breast tumor lacking hormone receptors and HER2 expression. However, in comparison with triple-negative invasive ductal carcinoma (TN-IDC), little is known about the PSCCB. Twenty-nine patients with PSCCB in Sun Yat-sen University Cancer Center from 1995 to 2010 were recruited in this study, along with 681 cases of TN-IDC during the same period. The clinicopathologic features and prognosis of PSCCB compared to TN-IDC were assessed. Furthermore, biomarkers of EGFR, CK5/6, E-cadherin, VEGF, TOPII, and p53 were immunostained to investigate the prognostic determinant of PSCCB. Patients with PSCCB were older than those with TN-IDC (P = 0.009) and presented with lower lymph node involvement (P = 0.015). There was no difference in overall survival (OS) between PSCCB and TN-IDC. However, the disease-free survival (DFS) of PSCCB was poorer than that of TN-IDC (P = 0.007). Multivariate analysis revealed that combined over-expression of EGFR and CK5/6 was the only independent prognostic factor for OS of PSCCB (HR 6.08, 95 % CI 1.33-27.85, P = 0.020) and associated with lymphatic metastasis (P = 0.023) and p53 expression (P = 0.013). Other predictors for poorer OS and DFS were lymphatic metastasis and stage III, which failed to show significance after multivariate analysis. Furthermore, platinum-based chemotherapy was identified to improve the OS of PSCCB with EGFR + CK5/6+ (P = 0.027). The prognosis of PSCCB is poorer than that of TN-IDC. As the only independent prognostic factor for PSCCB, combined over-expression of EGFR and CK5/6 might be a potential indicator for the use of platinum-based chemotherapy.