Leptin plays an important role in mammary tumor formation (Candida N Pereral et al., 2008 1). It is secreted by adipose tissue that acts on the brain to regulate energy expenditure and food intake and has an important role in energy balance, insulin pathway and inflammation. Hence the aim of our investigation has been to study the impact of Lep-2548G/A polymorphism in breast cancer as compared to matched controls. This study mainly focuses on the polymorphism leptin gene for variants by a screening this gene in south Indian obese subjects (n = 154 obese breast cancer cases and n=145 obese controls). We utilized PCR-RFLP based assay to evaluate the association between the Gln2548Arg polymorphism of the leptin gene and breast cancer risk in a case control study. The distributions of all three genotypes GG, GA and AA in breast cancer cases were 18.8%, 44.8%, and 36.4% compared to that of the controls, 33.0%, 29.6%, and 37.4%. We found that postmenopausal breast cancer cases showed statistically significant association with GA genotype when compared with premenopausal women without the disease (p= 0.001). This difference was between the cases and controls in the Gln2548Arg genotypes. Our findings suggest that the LEP Gln2548Arg polymorphism may be a useful biomarker associated with the risk of breast cancer women in Indian population.