Congenital generalized lipodystrophy type 1 (CGL-1) is characterized by an absence of adipose tissue and decreased serum leptin levels. Low leptin levels in CGL-1 support the claim that subjects are hypermetabolic and hyperphagic. The present study examines this claim. We determined 24-hour energy expenditure (24-h EE) (kilocalories) (n = 2) and resting metabolic rate (RMR) per kilogram of lean body mass (LBM) (n = 3) in CGL-1 and in 18 healthy control subjects. The 24-h EEs of control and subjects with CGL were compared with respect to kilocalories required per day relative to kilograms of LBM and with respect to RMR relative to kilograms of LBM. Fasting leptin, adiponectin, and 24-hour ghrelin levels were also measured in subjects with CGL-1. The 24-h EE per kilogram of LBM for the subjects with CGL-1 falls on the same regression line observed for this relationship in the controls. The RMR per kilogram of LBM in subjects with CGL-1 also was similar to that in controls. Both 24-h EE and RMR were quite increased when reported per kilogram of total body weight. Subjects with CGL-1 also have decreased fasting leptin and adiponectin hormone levels and no premeal ghrelin rise. People with CGL-1 have similar RMR and daily caloric requirements as healthy controls when these parameters are expressed as a function of LBM. Appetite-regulating hormone levels in CGL-1 suggest that multiple factors act to control appetite in these individuals.