Background and objectives : The most frequently detected life-threatening malignancy in women is breast cancer. We aimed to evaluate Sirtuin-1 mRNA and let-7b microRNA gene expression in breast cancer patients in Egypt and to relate them with clinicopathological features. Subjects & methods : The study recruited 225 female participants divided into the following groups: Group I: 75 patients histopathologically proven breast cancer, Group II: 75 patients histopathologically proven benign breast tumor; and Group III: 75 age matched healthy controls, from general surgery department at Menoufia University Hospital in Egypt. RT-qPCR was used to assess the expression levels of Sirtuin-1 mRNA and let-7b microRNA, while CA 15-3 was assessed by ELISA. Results: Let-7b microRNA was downregulated in breast cancer patients on comparison with benign breast tumors and control group (P< 0.001), and it was downregulated in patients with benign breast tumors compared to the control group (P <0.001). Sirtuin-1 mRNA was upregulated in the breast cancer patients compared to the benign breast tumor patients (p < 0.001) and control (p < 0.001) groups. Let-7b microRNA expression level was inversely correlated with tumor size (P=0.001; r =0.377) and affected lymph nodes (P<0.001; r=00.569). Moreover, Sirtuin-1 mRNA expression level was directly correlated with tumor size (P<0.001; r=0.438). Conclusion :Let-7b microRNA and Sirtuin-1 mRNA can be targeted for treatment and utilized as potential biomarkers for the earlier detection of breast cancer patients.