We hypothesized that, in children with homozygous sickle cell anemia (HbSS), the shortened life-span of erythrocytes places an increased demand on protein stores, accelerates whole body protein turnover, and consequently, energy expenditure, as well as the rate of utilization of glutamine, a major fuel for reticulocytes. Eight (11.2 +/- 0.4 y old) children with HbSS who were free of infection of vaso-occlusive disease, and seven (11.3 +/- 0.4 y old) healthy black children were therefore studied in the postabsorptive state. Each received a continuous 4-h infusion of L-[1-(13)C]leucine to determine the rate of leucine oxidation, leucine rate of appearance, and nonoxidative leucine disposal, indicators of whole body protein breakdown and synthesis, respectively. Infusion of L-[2-(15)N]glutamine was used to assess rates of glutamine utilization. Resting energy expenditure and cardiac output were measured using indirect calorimetry and echocardiography, respectively. Compared with control subjects, HbSS children had a 58 and 65% higher leucine rate of appearance and nonxidative leucine disposal, respectively (both p < 0.001), 47% higher rates of whole body glutamine utilization (p < 0.01), 19% higher resting energy expenditure (p < 0.05), and 66% higher cardiac output (p < 0.01). In conclusion, children with HbSS show evidence of hypermetabolism with regard to protein, energy, and glutamine utilization. Both increased Hb synthesis and increased cardiac workload may contribute to excess protein and energy utilization. Whatever the mechanism of hypermetabolism, the data suggest that children with HbSS may have greater protein and energy requirements than the general population.