Desaturation in patients with sickle cell anemia (SCA) can lead to intravascular sickling and vascular occlusion. The increased metabolic demands of exercise tend to increase oxygen extraction, giving rise to a fall in saturation in the capillary bed that may predispose to sickling. This could be minimized with an increase in cardiac output. The aims of this study were to assess the role of increased stroke volume (SV) in augmenting cardiac output (Q̇) and to estimate the role of enlarged arteriovenous O2 content difference in maintaining O2 transport in children with SCA. A group of 30 children with SCA (Hb 65 to 133 g/L) and 16 healthy controls of the same racial group and of similar height and weight performed incremental and steady-state exercise at 50% W(max). Cardiac output (Q̇) was measured by the indirect (CO2) Fick method during steady state. The slope of ΔHR/ΔV̇O2 during incremental exercise was higher in SCA subjects compared with controls (4.01 ± 1.73 versus 2.80 ± 0.61 bpm per ml/min/kg V̇O2, p = 0.001). Q̇ for V̇O2 was abnormally high in patients, particularly older ones with lower Hb levels. HR (% predicted) was higher in patients than in controls (106 ± 11 versus 92 ± 8% predicted, p < 0.0001), as was SV (113 ± 16 versus 98 ± 14% predicted, p = 0.002). Multiple linear regression of Q̇ % predicted and SV % predicted on Hb and age showed a positive correlation with age and a negative correlation with Hb (r = 0.84 for Q̇ and r = 0.76 for SV). The arteriovenous O2 content difference was larger in controls because of more available Hb, but the percentage of available O2 extracted at 50% Wmax was higher in SCA subjects. In conclusion, in children with SCA, SV enlarges disproportionately with growth, depending on the severity of anemia. The increase in Q̇ was not sufficient to prevent profound venous desaturation.