Multiple factors contribute to exercise intolerance in patients with sickle cell anemia, but little information exists regarding the safety of maximal cardiopulmonary exercise testing (CPET) or the mechanisms of exercise limitation in these patients. The purpose of the present study was to examine these issues. Seventeen adult women with sickle cell anemia underwent symptom-limited maximal CPET using cycle ergometry and ramp protocols; blood gases and lactate concentrations were measured every 2 minutes. All patients completed CPET without complications. No patient demonstrated a mechanical ventilatory limitation to exercise or had evidence of myocardial ischemia. However, we observed three pathophysiologic patterns of response to exercise in these patients. Eleven patients had low peak VO2, low anaerobic threshold (AT), gas exchange abnormalities, and high ventilatory reserve; this pattern is consistent with exercise limitation due to pulmonary vascular disease in this patient subgroup. Three patients had low peak VO2, low AT, no gas exchange abnormalities, and a high heart rate reserve, a pattern consistent with peripheral vascular disease and/or a myopathy. The remaining three patients had low peak VO2, low AT, no gas exchange abnormalities, and a low heart rate reserve; this pattern of exercise limitation is best explained by anemia.