• To define further the natural history and causative factors in exercise-related cardiac dysfunction in children and adolescents with sickle cell anemia (SS), we studied the results of 74 patients' initial and follow-up exercise tests. The follow-up study was done one to three years after the first study in 36 children and four to seven years after initial testing in 38 children. Split-plot analysis of covariance did not show any temporal deterioration in exercise hemodynamic variables. Correlation analysis defined hemoglobin and hematocrit levels as critical determinants of cardiac functional reserve capacity in these patients. Several exercise ECG patterns, formerly considered abnormal in children with SS, are now considered to be variants of normal. Studies are presently in progress that should further define the nature and severity of the cardiac impairment during exercise in children with SS.