Physiologic contributors to reduced exercise capacity in individuals with sickle cell anemia (SCA) are not well understood. The objective of this study was to characterize the cardiopulmonary response to maximal cardiopulmonary exercise testing (CPET) and determine factors associated with reduced exercise capacity among children and young adults with SCA. A cross-sectional cohort of 60 children and young adults (mean 15.1 +/- 3.4 years) with hemoglobin SS or S/beta(0) thalassemia and 30 matched controls (mean 14.6 +/- 3.5 years) without SCA or sickle cell trait underwent maximal CPET by a graded, symptom-limited cycle ergometry protocol with breath-by-breath, gas exchange analysis. Compared to controls without SCA, subjects with SCA demonstrated significantly lower peak VO2 (26.9 +/- 6.9 vs. 37.0 +/- 9.2 mL/kg/min, P < 0.001). Subjects demonstrated slower oxygen uptake (DeltaVO2/DeltaWR, 9 +/- 2 vs. 12 +/- 2 mL/min/watt, P < 0.001) and lower oxygen pulse (DeltaVO2/DeltaHR, 12 +/- 4 vs. 20 +/- 7 mL/beat, P < 0.001) as well as reduced oxygen uptake efficiency (DeltaVE/DeltaVO2, 42 +/- 8 vs. 32 +/- 5, P < 0.001) and ventilation efficiency (DeltaVE/DeltaVCO2, 30.3 +/- 3.7 vs. 27.3 +/- 2.5, P < 0.001) during CPET. Peak VO2 remained significantly lower in subjects with SCA after adjusting for age, sex, body mass index (BMI), and hemoglobin, which were independent predictors of peak VO2 for subjects with SCA. In the largest study to date using maximal CPET in SCA, we demonstrate that children and young adults with SCA have reduced exercise capacity attributable to factors independent of anemia. Complex derangements in gas exchange and oxygen uptake during maximal exercise are common in this population.