Children with Down syndrome (DS) have a high prevalence of obesity. To investigate the relation between energy expenditure and obesity, we measured body composition, resting metabolic rate (RMR), and total energy expenditure in 13 prepubescent children with DS and in 10 control subjects matched for age, weight, and percentage of fat, using indirect calorimetry and the doubly labeled water method. Measurement of RMR was complicated by excessive movement by both the DS and control subjects. We therefore developed a method of subtracting the energy expended in movement and calculated the corrected RMR. The corrected RMR was significantly lower in those with DS than in control subjects when expressed as a percentage of the basal metabolic rate, predicted by the World Health Organization: 79.5% +/- 10.4% and 96.8% +/- 7.8%, respectively (p < 0.001). No significant differences were detected in total daily energy expenditure or non-RMR expenditure between the subject groups. In the DS group, 60% of the variability in fat mass could be accounted for by non-RMR expenditure expressed per kilogram of body weight (p < 0.02). No relation was detected between fat mass and non-RMR expenditure in control subjects, nor were any measures of energy expenditure predictive of changes in fatness among the subjects with DS during a 1-year follow-up. The results of this study indicate that prepubescent children with DS have decreased RMR compared with control children.