CONTEXT: There is evidence that leptin is involved in the etiology of obesity-related cardiovascular disease in adults. This raises the question of whether leptin levels in adolescence are indicative of adiposity-related cardiovascular risk. OBJECTIVE: This study investigated gender-specific patterns of plasma leptin during adolescence, assessed which adiposity measurements are most strongly associated with plasma leptin, and estimated to what degree leptin-adiposity associations are influenced by genetic factors. METHODS: Plasma leptin concentrations were determined using a sandwich immunoassay. Associations between plasma leptin and several adiposity measurements were examined using generalized estimating equations. Genetic contribution to leptin-adiposity association was estimated by Cholesky decomposition models using twin design. RESULTS: Plasma leptin levels were higher in females than males at all Tanner stages. In females, body mass index, waist circumference, fat mass index (FMI), and percentage body fat (%BF) had similar associations with leptin levels. In males, %BF and FMI were more strongly associated with leptin levels than body mass index and waist circumference. In both males and females, percentage trunk fat had the weakest association with leptin among the five adiposity measures. Shared genetic factors account for more than 80% of the phenotypic correlation between %BF and leptin. CONCLUSIONS: We found gender differences in leptin levels and leptin-adiposity associations. In both genders, leptin levels were strongly associated with %BF and FMI, particularly in males. Shared genetic factors contributed largely to the phenotypic correlation between leptin and %BF. Our findings underscored the importance of further investigation of leptin as a biomarker of adiposity in adolescents.