The partial malaria resistance of sickle cell trait (HbA/S) carriers is conferred by the detection and clearance of erythrocytes infected with early (ring) stages of Plasmodium falciparum. Erythrocytes infected with later stages (trophozoites/schizonts) evade and suppress the immune system by tissue sequestration and formation of hemozoin, respectively. Ring stage-infected human HbA/S erythrocytes exhibit higher PGE2 formation, Ca2+ permeability, cell shrinkage and phosphatidylserine (PS) exposure in the external membrane leaflet than infected normal (HbA/A) erythrocytes. To test whether PGE2-stimulated PS exposure is an 'eat me' signal for macrophages we performed in vitro phagocytosis and in vivo clearance experiments. As a result, PS- exposing fluorescence-labeled mouse erythrocytes were rapidly cleared from peripheral blood and sequestered in the spleen while normal erythrocytes remained in circulating blood for several days. Masking the externalized PS by coating with AnnexinV protein prior to re-transfusion significantly delayed the clearance and the spleen sequestration of the PS-exposing cells. In addition, ring-infected HbA/S cells were phagocytized by human monocytes/macrophages more rapidly than HbA/A cells. Masking of PS abolished this difference. In conclusion, accelerated PS exposure of ring stage-infected HbA/S erythrocytes results in detection and clearance by the innate immune system and thus contributes to the partial resistance of sickle cell trait carriers.