Background: Nesfatin-1, an anorexigenic peptide, has been associated with food intake and thermogenesis, with discordant findings in humans and scarce studies in children to date., Objectives: The aim of this study was to analyze the relationship of obesity with nesfatin-1 levels in two cohorts of children., Methods: Plasma nesfatin-1 concentrations were analyzed in 6- to 9-year-olds (n = 140) and 12- to 16-year-old children (n = 96), including children with obesity and their sex- and age-matched normal-weight counterparts. Anthropometric measurements were assessed. Cholesterol and triglycerides were determined enzymatically, insulin concentrations were measured by radioimmunoassay using a commercial kit and nesfatin-1, leptin and hs-CRP concentrations were determined using commercial ELISA kits., Results: Nesfatin-1 concentrations were significantly lower in younger (P = .001) and older (P = .009) girls with obesity than in their normal-weight counterparts, without showing significant differences in boys. Nesfatin-1 showed a negative significant (P < .010) correlation with weight and BMI in girls but not in boys. A significant positive correlation of nesfatin-1 levels with insulin, HOMA, and leptin levels appears in girls after adjusting by age and BMI. A significant positive correlation (P = .003) was observed between nesfatin-1 and fat mass in older children., Conclusions: Our study shows lower concentrations of nesfatin-1 related to obesity in girls but not in boys at two different ages. The existence of a sex-specific association between nesfatin-1 concentrations and presence of obesity highlights the need of an analysis by gender of the relationship of nesfatin-1 with obesity., (© 2019 World Obesity Federation.)