Objective: Ghrelin and polipeptide YY (PYY) are involved in the regulation of food intake. We evaluated these two peptides and their possible relationship in adult patients with Prader-Willi syndrome (PWS). Patients: Seven patients with PWS, 16 age-sex-BMI matched obese and 42 age-sex matched lean subjects. Design and measurements: Fasting plasma PYY and ghrelin levels were measured in all subjects and, postprandially until 6 h, in seven matched subjects of each group. Results: Fasting ghrelin levels were higher in PWS than in the other two groups. Fasting PYY levels were lower in patients with PWS than in lean subjects but similar to those in obese subjects. The postprandial decrease in ghrelin concentrations was lower in PWS as compared to the other two groups and therefore the 6-h-postprandial area under the curve (AUC) for ghrelin was higher in PWS than in obese subjects. PYY response after the meal was blunted in patients with PWS, but not in the other two groups that showed a peak at 60 min The AUC for PYY was lower in PWS as compared to the other two groups. Fasting PYY levels correlated negatively with fasting ghrelin levels and with ghrelin AUC and they were the only predictor for ghrelin AUC (β = -0.464, P = 0.034). The increase in PYY correlated negatively with the decrease in ghrelin at times 60 min and 120 min in PWS. Conclusions: In PWS, the low decrease in postprandial ghrelin levels could be related to the low fasting PYY concentrations and their blunted postprandial response. © 2006 The Authors.