Triple-negative breast cancer (TNBC) has an aggressive behavior and limited therapeutic options due to lack of targeted therapy. We aimed in this study to assess the immunohistochemical expression of EGFR and cytokeratin 5/6 and their ability to predict survival and response to neoadjuvant chemotherapy (NAC) among triple-negative breast cancer patients. Thirty-five cases with TNBC were studied by immunohistochemistry for EGFR and CK5/6 expression. Data on overall survival (OS), disease-free survival (DFS) and response to NAC were collected. The resulted data were statistically analyzed. Invasive carcinoma of no special type (NST) was the predominant histopathological type (80%). The commonest histological grade was grade II-III (88.6%). About 57.1% of TNBC cases were CK5/6-positive, and 71.4% were EGFR-positive. EGFR expression showed a significant association with tumor grade and axillary lymph node metastasis (p = 0.006, 0.016 respectively). EGFR expression was related to unfavorable response to NAC (p = 0.036), poor OS (p = 0.002) and poor DFS (p = 0.003). CK5/6 expression showed a significant association with tumor grade, unfavorable response to NAC, poor OS & DFS (p = 0.007, 0.048, b0.001, 0.043 respectively). Immunohistochemical expression of EGFR and/or CK5/6 showed a high significant association with an unfavorable response to NAC, poor DFS &OS (p = 0.010, 0.012, 0.030 respectively). Conclusions: EGFR and CK5/6 are adverse prognostic markers in TNBC. EGFR and CK5/6 expression could serve as biomarkers for identifying TNBC patients with poor survival that are unlikely to benefit from neoadjuvant chemotherapy. So, targeted therapy against EGFR may be a hopeful therapy for TNBC with NAC resistance.