Adults with sickle cell anemia (SCA) have restrictive lung impairment, increased alveolar dead space, and hypoxemia. These factors, together with increased anaerobic metabolism, are thought to cause exercise hyperventilation. To assess the role of each of these in children, 34 patients with SCA and 16 control subjects performed pulmonary function and exercise tests. Twenty-eight patients with SCA had spirometric values and lung volumes, and all but two patients with SCA had arterial saturation >91% during exercise. Despite a low V̇O2max (30.07 ± 6.55 ml/min/kg), the ventilatory anaerobic threshold (VAT) in the patients occurred at a similar %V̇O2max as in the control subjects (69 ± 9% versus 63 ± 12%). The slope of the ΔV̇E/ΔV̇CO2 relationship for sub-VAT work was steeper in the patients (29.4 ± 6.5 versus 24.7 ± 5.2, p = 0.01), and the ventilatory equivalent for CO2 (V̇E/V̇CO2) in steady-state exercise was greater in the patients than in the control subjects (33.2 ± 3.5 versus 30.8 ± 3.5, p = 0.03). End-tidal PCO2 did not differ (38.3 ± 3.0 versus 39.2 ± 3.1), indicating equivalent alveolar ventilation. The patients had a higher dead space:tidal volume ratio (VD/VT) than did the control subjects (0.204 ± 0.033 versus 0.173 ± 0.024, p = 0.0005). The PaCO2 was significantly lower in those with lower Hb, but there was no difference in pH. In conclusion, children with SCA have an increased exercise ventilatory response caused in part by increased physiologic dead space, and in part by their low Hb. The greater dead space may be the result of sickle cells impairing capillary perfusion to ventilated alveoli.