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Aim: Elevated calprotectin levels have been reported in obese adults but have not been evaluated in pediatric population. We investigated the characteristics of serum calprotectin in overweight and obese children and its association with metabolic comorbidities. Methods: We enrolled 131 children (11.7 ± 4.1 years). According to body mass index (BMI), the subjects were divided into 3 groups: obese > 95th percentile; overweight BMI 75th–95th percentile, and normal weight BMI < 75th percentile. Patients were classified as having Metabolic Syndrome if they met 3 or more of the following criteria for age and sex: BMI > 97th percentile, triglycerides > 95th percentile, high-density lipoprotein cholesterol < 5th percentile, systolic and/or diastolic blood pressure > 95th percentile, and impaired glucose tolerance. In all patients, calprotectin serum levels were also detected. Results: Calprotectin was higher in obese and overweight children than normal weight subjects (p < 0.001), with calprotectin in females being significantly higher than in males (p = 0.04). Increased calprotectin was related to pathological fasting blood glucose (p < 0.001) and insulin resistance (p = 0.03), while BMI (p = 0.001), and diastolic pressure (p = 0.001) are independent factors for increased calprotectin. Conclusions: Our findings confirm the association between increased calprotectin and obesity also in children and suggest the potential utility of this biomarker in the monitoring of its metabolic complications.