To determine if hemoglobin E trait influences the course of acute malaria, adults hospitalized for the treatment of symptomatic infection with Plasmodium falciparum were studied retrospectively. Forty-two patients with hemoglobin E trait were compared with 175 reference subjects who did not have hemoglobin E, beta-thalassemia, glucose-6-phosphate dehydrogenase deficiency, or alpha-thalassemia. One patient (2.4%) with hemoglobin E trait had a severe complication of malaria by World Health Organization criteria (cerebral malaria), while 32 subjects in the reference group (18.3%) had one or more severe complications: cerebral malaria (n=18), hyperparasitemia (n=16), renal failure (n=10), and severe anemia (n=1) (P=.044 after adjustment for ethnic categories). The estimated odds of severe complications in the reference subjects were 6.9 times the odds in patients with hemoglobin E trait (95% confidence interval, 1.2-146. 4). These results suggest that hemoglobin E trait may ameliorate the course of acute falciparum malaria.