Background: Recently, the prevalence of thyroid cancer has increased. Although there are known risk factors for thyroid cancer, none of them can justify this recent increase. In addition to the known risk factors, other risk factors have been proposed. Leptin can be considered as one of these risk factors due to the recent increase in the prevalence of obesity in the population. Leptin is a common factor in obesity and thyroid cancer. Leptin exerts anti-apoptotic and mitogenic effects on cancer cells and also acts as an angiogenic factor. This study aimed to evaluate the serum leptin level in individuals who suffer from papillary thyroid carcinoma (PTC), cases with benign thyroid nodules (BTN), and a healthy group. Materials and Methods: In this study, newly diagnosed patients with PTC, BTNs, as well as euthyroid healthy control subjects without nodules were included. In all these participants, various clinical and laboratory parameters including thyroid function tests and serum leptin levels were measured and compared between the three study groups. For patients with PTC, leptin was assessed 12 weeks after total thyroidectomy. Results: Ninety-one cases with PTC, 90 cases with BTNs, and 88 controls were recruited. Serum leptin levels in the PTC group, benign group, and the control group were 22.34, 17.60, and 13.83 ng/ml, respectively, which was considerably higher in PTC cases compared to those with benign nodules and control group (P<0.001). There was a significant association between leptin with BMI, tumor size, and tumor stage in PTC patients. Also, in patients with BTNs, a correlation between BMI, tumor size, and leptin was observed. Conclusion: Serum leptin levels were considerably higher in cases with PTC than those with BTNs and controls and can be considered as a potential tumor marker for papillary thyroid cancer.