Leptin hormone and receptor have been associated to cancer development and were identified in lung tissue. In this study, a functional polymorphism in the 5' flanking region of the leptin gene (LEP -2548 G/A) was found to increase susceptibility for non-small cell lung cancer [odds ratio (OR), 1.97; 95% confidence interval (CI), 1.13-3.43]. Age-adjusted logistic regression analysis in men indicated an association of AA genotype with adenocarcinoma (OR, 4.29; CI, 1.64-11.72) and squamous cell carcinoma (OR, 3.19; CI, 1.26-8.13). Logistic regression analysis confirmed the AA genotype as an independent risk factor for lung cancer after adjustment for age and gender (OR, 2.57; CI, 1.34-4.92). The AA genotype was overrepresented only in patients with non-metastatic disease (OR, 1.86; CI, 1.13-3.04). Kaplan-Meier analysis demonstrated an earlier age of onset for lung cancer in AA carriers (P=0.023). Results suggest the existence of genetic susceptibility for lung cancer in carriers of this LEP functional polymorphism. Further studies are warranted to extend knowledge of leptin involvement in lung cancer.