Background: Breast cancer is the most common cancer in Egyptian women. COX-2 seems to be involved in malignant transformation and tumor progression by affecting cell proliferation, mitosis, cell adhesion, apoptosis, immune surveillance, and angiogenesis. Angiogenesis is an important key step in tumor progression. Microvascular density (MVD), a surrogate marker of angiogenesis can be assessed by CD31 staining. Aims This study aims to: 1. Evaluate COX-2 and CD31 expressions in breast cancer. 2. Determine the correlation between COX-2 and CD31 with the clinico-pathological parameters in ductal breast carcinoma. Materials and Methods: This study included 74 specimens of breast lesions. Patient’s age, tumor size and local aggressive changes, history of recurrence and/or presence of distant metastasis were obtained. 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 CD31 immunostaining was done to detect their expression using the avidin-biotin peroxidase method. Results: COX-2 increased with increasing grade of ductal carcinoma in situ (DCIS) and invasive ductal carcinomas (IDC) (P< 0.05 and P< 0.002 respectively). COX-2 expression increased progressively along the continuum of neoplastic changes from normal breast epithelium to IDC (P< 0.01). There was significant correlation between COX-2 and tumor size (P< 0.05), tumor grade (P< 0.002), lymphovascular invasion (P< 0.03) and lymph node metastasis (P< 0.02). CD31 staining was observed along the cell membrane of endothelial cells of microvessels in all breast specimens. The median CD31 MVD count was 10 for normal breast, increased insignificantly to 17 in hyperplastic lesions, and reached 19 for DCIS, and 66.5 in IDC (P < 0.000). There was significant increase in MVD between different grades of IDC (P < 0.01) but not in DCIS. Positive correlation was present between COX-2 & CD31 in DCIS and in IDC (P <0.000 for each). Conclusion: COX-2 was increased with poor prognostic parameters; tumor size, tumor grade, lymphovascular invasion and lymph node metastasis. CD31 increases with increasing grade of IDC. These findings might imply for new therapeutic strategies in order to prevent progression of DCIS to IDC and to improve cancer therapy