In the present study, energy expenditure (EE) and rates of whole-body protein, glucose, and lipid metabolism were assessed in 8 African American sickle cell disease (SCD) patients and in 6 healthy African American control subjects during the infusion of amino acids, glucose, and lipid. Whole-body protein, glucose, and lipid kinetics were estimated by using L-[1-(13)C]leucine, D-[6,6-(2)H2]glucose, and [(2)H5]glycerol, respectively. After a 2-h tracer equilibration period and a 0.5-h basal period, nutrients were administered intravenously for 3 h with 16% of the energy as protein, 52% as carbohydrate, and 32% as fat. Breath and blood were collected during the last 30 min of nutrient infusion and EE was measured by indirect calorimetry. EE was 14% greater (P < or = 0.05) in SCD patients [145.0 +/- 3.5 kJ x kg fat-free mass (FFM)(-1) x d(-1)] than in control subjects (126.8 +/- 3.8 kJ x kg FFM(-1) x d(-1)). Whole-body protein breakdown (4.4 +/- 0.4 compared with 3.1 +/- 0.1 mg x kg FFM(-1) x min(-1), P < or = 0.05) and protein synthesis (4.6 +/- 0.4 compared with 3.2 +/- 0.1 g x kg FFM(-1) x min(-1), P < or = 0.05) were 42% and 44% greater, respectively, in the SCD patients than in control subjects, but whole-body amino acid oxidation (0.90 +/- 0.05 compared with 1.03 +/- 0.09 mg x kg FFM(-1) x min(-1)) was not significantly different between the 2 groups. Whole-body glucose and lipid kinetics did not differ significantly between the groups. EE increased in SCD patients during exogenous nutrient availability, and the additional energy required for the accelerated rates of whole-body protein breakdown and synthesis made a significant contribution to the increase in EE. These metabolic aberrations may increase the dietary energy and protein requirements of SCD patients.