Background: Breast cancer is the most common malignancy in women and its increasing incidence is a challenge worldwide. Obesity has been linked to an increased risk of developing a number of malignancies, including postmenopausal breast cancer. The link between obesity and breast cancer involves elevated estrogen production and adipokines secretion that affect tumorigenesis. Objective: We investigated whether genetic variations in the Leptin (LEP) and CYP19A1 genes are associated with risk of breast cancer among Egyptian postmenopausal women. Methods: This is a case control study. It included 112 postmenopausal breast cancer patients and 112 healthy postmenopausal controls .The LEP(-2548G>A) and CYP19A1 (rs10046C/T) gene polymorphisms were determined using polymerase chain reaction-based restriction fragment length polymorphism and Tetra Amplification refractory mutation system - polymerase chain reaction ,respectively. Results: Significant difference between postmenopausal breast cancer women and controls regarding allele and genotype distributions of LEP(-2548G>A) (OR 1.8 , 95 % CI 1.23–2.73 and p=0.007 for A allele) and CYP19A1 (rs10046C/T) polymorphisms (OR 1.9, 95 % CI 1.27–3.8, and p = 0.004 for T allele). Moreover, stratified analysis of these polymorphisms in relation to body mass index revealed interactive effect between LEP (-2548G>A) and BMI for the breast cancer risk. Conclusion: The results suggest that the AA genotype and A allele of leptin polymorphism, as well as the TT genotype and T allele of the CYP19A1 polymorphism, may be associated with increased risk of the development of breast cancer, Moreover obese postmenopausal breast cancer patients carrying LEP A allele have 3 fold risk to develop breast cancer in the Egyptian population.