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The goal of our study was to determine the expression and phosphorylation of PTEN at residues Ser380/Thr382/383, as well as the nuclear expression of p53 in Sudanese patients with breast cancer (BC) in association with clinicopathological aspects of BC. Methods and Results: This retrospective, descriptive study was carried out in Wad-Madani, Gezira state in Sudan, from January 2015 to August 2016. A total of 179 biopsies were taken at random from patients with breast lesions. Two blocks were obtained for each patient. One came from a malignant lesion (Group A), whereas the other came from the margin adjacent to healthy tissue (Group B). Immunohistochemistry and immunofluorescent histochemistry were performed on two separate slides. We found a statistically significant difference in the frequency of immunohistochemical expression of p53 and phosphorylation of PTEN between the cancerous breast tissue and adjacent normal tissue. P53 and PTEN exhibited a significant relationship with each other and the grade of tumor, indicating their importance in the aggressiveness of breast lesions. It should also be emphasized that there is an association between p53 expression and lymph node metastasis, which indicates the involvement of p53 mutation in the metastasis of BC.