Erythrocyte polymorphisms associated with a survival advantage to Plasmodium 
falciparum infection have undergone positive selection. There is a predominance 
of blood group O in malaria-endemic regions, and several lines of evidence 
suggest that ABO blood groups may influence the outcome of P. falciparum 
infection. Based on the hypothesis that enhanced innate clearance of infected 
polymorphic erythrocytes is associated with protection from severe malaria, we 
investigated whether P. falciparum-infected O erythrocytes are more efficiently 
cleared by macrophages than infected A and B erythrocytes. We show that human 
macrophages in vitro and mouse monocytes in vivo phagocytose P. 
falciparum-infected O erythrocytes more avidly than infected A and B 
erythrocytes and that uptake is associated with increased hemichrome deposition 
and high molecular weight band 3 aggregates in infected O erythrocytes. Using 
infected A(1), A(2), and O erythrocytes, we demonstrate an inverse association 
of phagocytic capacity with the amount of A antigen on the surface of infected 
erythrocytes. Finally, we report that enzymatic conversion of B erythrocytes to 
type as O before infection significantly enhances their uptake by macrophages to 
observed level comparable to that with infected O wild-type erythrocytes. These 
data provide the first evidence that ABO blood group antigens influence 
macrophage clearance of P. falciparum-infected erythrocytes and suggest an 
additional mechanism by which blood group O may confer resistance to severe 
malaria.