A substantial number of reports of cases and small investigations support blood exchange transfusion as a therapy for hyperparasitemia in cases of Plasmodium falciparum malaria, although a prospective and randomized study has never been undertaken. We report on 113 prospectively enrolled children in Lambaréné, Gabon, who had more than 10% parasitized erythrocytes and were treated with chemotherapy alone. All 86 patients with hyperparasitemia as the sole complication recovered uneventfully. Among the 27 patients who had additional complications, parasitemia levels as high as 81% responded well to chemotherapy alone. Two patients with cerebral malaria, who also had other complications and hence a poor prognosis, died. Hyperparasitemia itself might be important for the development of a fatal event in malaria, but a recommendation to perform a dangerous, expensive, and labor-intensive procedure such as blood exchange transfusion for its treatment should be based on substantial clinical research, especially in areas where malaria is a major health problem.