Prader–Willi syndrome (PWS) is an obesity syndrome characterized by rapid weight gain and excessive food intake. Food intake is regulated by the hypothalamus but directly influenced by gastrointestinal peptides responding to the nutritional status and body composition of an individual. Ghrelin, derived from preproghrelin, is secreted by the stomach and increases appetite while obestatin, a recently identified peptide derived post‐translationally from preproghrelin, works in opposition to ghrelin by decreasing appetite. The objective of this study was to measure fasting obestatin and ghrelin levels in peripheral blood of subjects with PWS and compare to age and gender matched control subjects. Plasma obestatin and ghrelin levels were measured in subjects with PWS (n = 16, mean age = 16.0 ± 13.3 years; age range 1–44 years) and age and gender matched control subjects (n = 16). Significantly higher obestatin levels were seen in the 16 PWS subjects (398 ± 102 pg/ml) compared with 16 controls (325 ± 109 pg/ml; matched t‐test, P = 0.04), particularly in 5 young (≤3 years old) PWS subjects (460 ± 49 pg/ml) compared with 5 young controls (369 ± 96 pg/ml; matched t‐test, P = 0.03). No significant difference in ghrelin levels was seen between the PWS and comparison groups. No significant correlation was observed for either peptide when compared with body mass index but a significant negative correlation was seen for ghrelin and age in PWS subjects. Our observations suggest that obestatin may be higher in infants with PWS compared to comparison infants. The possibility that obestatin may contribute to the failure to thrive which is common in infants with PWS warrants further investigation. © 2007 Wiley‐Liss, Inc.