Background/Aims: Breast cancer is the most common cancer in Egyptian women. This study aims to: 1. Evaluate COX-2 and p53 expressions in the successive steps of breast carcinogenesis. 2. Determine the correlation between COX-2 and p53 with the clinico-pathological parameters in ductal breast carcinoma. Patients and Methods: This study included 74 specimens of breast lesions. Data about patient’s age, tumor size and local aggressive changes, history of recurrence and/or presence of distant metastasis were obtained from clinical sheets. Hematoxylin and Eosin (H&E) stained sections were evaluated for histopathological tumor type, tumor grade, presence or absence of normal, hyperplastic, in situ component, lymphocytic infiltration, lymphovascular invasion, and axillary lymph node status. COX-2 and p53 immunostaining was done to detect their expressions using the avidin-biotin peroxidase method. Results: COX-2 and p53 expressions increased with increasing grade of ductal carcinoma in situ (DCIS) and invasive ductal carcinomas (IDC) (P< 0.05 and P< 0.002 respectively for COX-2) and (P< 0.01 and P< 0.002 respectively for p53). COX-2 and p53 expressions increased progressively along the continuum of neoplastic changes from normal breast epithelium to IDC (P< 0.01 for each). There was significant correlation between either COX-2 or p53 and tumor size (P< 0.05 for each), tumor grade (P< 0.002 for each), lymphovascular invasion (P< 0.03 & <0.02 respectively). There was significant correlation between COX-2 and lymph node metastasis (P< 0.02). There was significant correlation between p53 and lymphocytic infiltration (P< 0.03). There were positive correlations between COX-2 and p53 in DCIS and in IDC (P <0.000 for each). Conclusion: Both COX-2 and p53 were increased with poor prognostic parameters; tumor size, tumor grade, lymphovascular invasion, lymph node metastasis and lymphocytic infiltration. P53 is likely to be involved in the regulation of COX-2 expression in ductal breast cancer. These findings might imply for new therapeutic strategies in order to prevent progression of DCIS to IDC and to improve breast cancer therapy