The effects of dietary macronutrients on orexigenic and anorexigenic hormones in children are poorly understood.To explore effects of varying dietary macronutrients on appetite-regulating hormones [acyl ghrelin (AG) and desacyl ghrelin (DAG), glucagon-like peptide 1 (GLP-1), peptide tyrosine tyrosine (PYY), and insulin) in children with PWS and healthy children (HC).Randomized, cross-over experiments compared two test diets [High Protein-Low Carbohydrate (HP-LC) and High Protein-Low Fat (HP-LF)] to a STANDARD meal (55% carbohydrate, 30% fat, 15% protein). Experiment 1 included ten children with PWS (median age 6.63y; BMI z 1.05); experiment 2 had seven HC (median age 12.54y; BMI z 0.95). Blood samples were collected at baseline and at 60-minute intervals for 4 hours. Independent linear mixed models were adjusted for age, sex, and BMI z-score.Fasting and post-prandial AG and DAG concentrations are elevated in PWS children; the ratio of AG/DAG is normal. Food consumption reduced AG and DAG concentrations in both PWS and HC. GLP-1 levels were higher in PWS after the HP-LC and HP-LF meals than the STANDARD meal (p = 0.02- 0.04). The fasting proinsulin to insulin ratio (0.08 vs. 0.05) was higher in children with PWS (p=0.05) than in HC. Average appetite scores in HC declined after all three meals (p = 0.02) but were lower after the HP-LC and HP-LF meals than the STANDARD meal.Altered processing of proinsulin and increased GLP-1 secretion in children with PWS after a high protein meal intake might enhance satiety and reduce energy intake.