Background: The relationship between thyrotropin (TSH) concentrations and body mass index (BMI) in euthyroid subjects has been demonstrated only in some studies. Leptin regulates TSH secretion and TSH stimulates leptin secretion. The main aims of our study were to assess the relationship between leptin, the thyroid axis, and thyroid autoimmunity in a representative sample of a nonhospitalized euthyroid adult population of Catalonia and to determine whether smoking status could influence this relationship. Methods: This cross-sectional population-based study includes 894 euthyroid iodine-sufficient adults (390 men, 44.87±15.03 years old) with BMI 26.19±4.61 kg/m2, representative of people living in Catalonia. The study analyzes the relationship between TSH, free thyroxine (FT4), leptin, thyroperoxidase and/or thyroglobulin antibodies (thyroid autoimmunity), smoking status, and BMI. Measurements also include glycemia and insulinemia to calculate homeostasis model assessment of insulin resistance (HOMA-IR) index as a measure of insulin sensitivity. Results: In the univariate analysis and in the overall group, TSH correlated directly with BMI, leptin, and HOMA-IR (p=0.039, p<0.001, and p=0.010, respectively). In all men, TSH correlated directly with leptin (p=0.004), and in all women, directly with leptin (p=0.002) and HOMA-IR (p=0.031) and inversely with FT4 (p=0.024). Only in men who smoke, TSH correlated directly with leptin (p=0.010) and HOMA-IR (p=0.024). In women, TSH correlated directly with leptin (p=0.004) and in nonsmoking women, inversely with FT4 (p=0.047). In the multiple regression analysis, age (β=-0.00310, p=0.0265), smoking status (β=-0.24085, p=0.0202), and thyroid autoimmunity (β=0.20652, p=0.0075) were independent predictors of TSH variations. Leptin was a significant independent predictor of TSH variations only in smokers (β=0.16451, p=0.047). Conclusions: Leptin is an independent predictor of TSH concentration variations only in euthyroid smoker subjects of both sexes at all ranges of BMI, but not in nonsmokers. Age, smoking status, and positive thyroid autoimmunity also influenced TSH variability. © Copyright 2013, Mary Ann Liebert, Inc. 2013.