There is limited information on the underlying physiological mechanisms promoting obesity in patients with Prader-Willi syndrome (PWS). The aim of this study was to investigate whether body fat regulation in children with PWS is similar to that in children with nonsyndromal obesity and non-obese children. We studied three groups: 1) 72 non-obese children and adolescents; 2) 68 children with nonsyndromal obesity; and 3) 11 patients with PWS. Height and weight were measured and body mass index (BMI) and BMI SDS were calculated. Fasting serum leptin concentrations were determined. Median leptin serum concentrations were similar in PWS patients and children with non-syndromal obesity. Median leptin serum concentrations were higher in these two groups than in the non-obese group. Log leptin serum concentrations and BMI SDS showed significant correlations in the three groups of patients; correlation coefficients were 0.525, 0.285 and 0.854, respectively. In conclusion, median leptin serum concentrations are similar in PWS patients and children with non-syndromal obesity. The relationship between log serum leptin concentrations and BMI SDS was different in the three groups of patients studied.