Prader-Willi syndrome is characterized by dramatic hyperphagia and morbid obesity, and is associated with a deficiency in basal and meal-stimulated serum pancreatic polypeptide (PP) levels. Intravenous infusions of pancreatic polypeptide (90 min, 50 pmol/kg/h) restored normal serum PP levels, and a regimen of morning and afternoon PP infusions was found to significantly reduce food intake in Prader-Willi subjects. Food intake was evaluated in a 60-min free-feeding test that shows high reliability and validity. Basal food intake during saline infusions was striking (approximately 60 chicken sandwich quarters), and this intake was reduced overall by approximately 12% during PP infusions. This reduction was apparent only for female subjects, and may have reflected enhanced satiation rather than an overall suppression of food intake. No differences were apparent across subjects, in either basal food intake or the PP-related decrease in food intake, in the presence or absence of the widely recognized chromosomal marker for this syndrome [deletion of 15(q11-q13)]. More specific gene defects as recently reported in these subjects, however, suggest that the Prader-Willi syndrome may represent an important model for the study of food intake regulation.