Prader-Willi Syndrome (PWS) is a genetic disorder characterised by developmental and growth abnormalities, insatiable appetite, and excessive eating (hyperphagia) that presents in early childhood. Without strict parental control of food intake, children with PWS develop morbid obesity and associated diseases and face a shortened lifespan. Hyperphagia in PWS is thought to be driven by supraphysiological levels of the appetite hormone ghrelin. The underlying causes of hyperghrelinaemia in PWS are currently unknown. Recently, ghrelin-reactive autoantibodies (IgG) were identified in non-genetic obesity. These autoantibodies reversibly bind to circulating ghrelin and protect it from degradation, thereby potentiating its orexigenic effects, and represent a novel target for appetite control1. In this study we measured levels of ghrelin and ghrelin-reactive IgG in children with PWS compared to body mass index (BMI) and age-matched unaffected children after an overnight fast and following a standardized meal at five postprandial time points. Linear epitope mapping was also performed to determine the autoantibody target regions. As anticipated, children with PWS displayed fasting hyperghrelinaemia and increased fat mass compared to controls (P<0.05, t test). Fasting and postprandial plasma ghrelin-reactive autoantibody levels were increased in children with PWS compared to controls (P<0.01, two-way ANOVA). Ex vivo pre-absorption of plasma with an inactive isoform of ghrelin reduced the level of ghrelin-reactive autoantibodies detected in both cohorts (P<0.01, paired t test), suggesting that the autoantibodies can be targeted by inactive “decoy” peptides. Epitope mapping, including alanine scanning mutagenesis, revealed that autoantibodies from PWS patients bound to several unique epitopes compared to controls and that the epitope landscape was remarkably consistent across the PWS cohort. In conclusion, increased levels of ghrelin-reactive autoantibodies in PWS may contribute to the hyperghrelinaemia and hyperphagia that characterises the syndrome. Targeting these autoantibodies and their unique epitopes may provide a future therapeutic avenue for this incurable disorder.