Patients with Prader-Willi syndrome are frequently obese. To determine if obesity is partially explained by a low energy expenditure, we compared total daily energy expenditure, basal metabolic rate, and body composition in Prader-Willi patients with obese controls. Total energy expenditure was measured by doubly labeled water, basal metabolic rate was measured by respiratory gas analysis using an open-system canopy design, and body composition was calculated from total body water determinations using 18O labeled water. In six Prader-Willi subjects, basal metabolic rates were normal when compared on the basis of fat free mass, but not body surface area or height, weight, and age. Ten Prader-Willi subjects (8 to 24 years-old) had a total daily energy expenditure (+/- SD) of 1,980 +/- 580 kcal/d, which was 47% less than their obese controls (3,700 +/- 820 kcal/d). When normalized for their smaller fat free mass and body mass, however, the difference was only 14% (P less than .01). The results indicate that the low energy expenditures in Prader-Willi syndrome are mostly due to the small fat free mass in these patients and not due to any difference in energy efficiency at the cellular level. Prader-Willi subjects who had lost weight and were at or near weights appropriate for their heights were still 30% to 40% body fat. Because this excess fat was not evident from skinfold measures, usual anthropometric measures were not reliable indicators of total body fat in these subjects.