CONTEXT: Spexin is a novel peptide that is implicated in obesity and related energy homeostasis in animals and adult humans. Little is known about its role in children. OBJECTIVE: The aim of the current study was to determine the potential role of Spexin in obese children and explore its relationships with various cardiometabolic risk factors. DESIGN AND PARTICIPANTS: This was a cross-sectional study composed of 69 children (51 obese and 18 normal weight; age 15.3 +/- 0.26 y). OUTCOME MEASURES: Spexin was measured using a specific enzyme-linked immunosorbent assay. Leptin, total and high-molecular-weight adiponectin, IL-6, high-sensitivity C-reactive protein, glucose, and insulin were also measured. Mann-Whitney U test, Pearson and Spearman rank correlations, logistic regression, and cluster analysis were used for the analysis and interpretation of the data. RESULTS: Spexin levels were significantly lower in obese vs normal-weight children, median (IQR) (0.33 ng/mL [0.27-0.44] vs 0.42 ng/mL [0.33-0.55]; P = .024), but did not correlate with other adipokines and/or insulin and glucose levels. Ordinal categorical variables of Spexin showed a strictly reverse association of obesity with the level of Spexin. Cluster analysis of Spexin and body mass index z score resulted in splitting the participants into normal-weight and obese-weight groups with high accuracy. CONCLUSIONS: Lower circulating levels of Spexin in obese children compared with their normal-weight counterparts and the ability to discriminate obese and normal-weight groups based on Spexin concentration enabled us to suggest a potential role for this novel peptide in childhood obesity. The clinical significance of these findings needs additional investigation.