Protective mechanisms of genetically variant erythrocytes against Plasmodium falciparum infection has been studied in two ways : 1) the susceptibility of P. falciparum in the variant erythrocytes to exogenous oxidative stress, 2) the sialic acid content and distribution on the erythrocyte membranes. The study of susceptibility of P. falciparum in these abnormal erythrocytes to exogenous oxidant H(,2)O(,2), generated from reaction of glucose/glucose oxidase (GO), was used in simulation of secreted products of monocytes during phagocytosis process. It was found that the malaria parasite in G6PD deficient erythrocytes (n=14) had markedly increased degree of susceptibility, comparing to that in normal erythrocytes (n=14), to a wide range of Go used. The parasite in (...) thalassemia(,1)/hemoglobin Constant Spring ((...)thal(,1)/HbCS, n=4), (...)thal(,1)/ thal(,2) (n=4),(...)thal/HbE (n=7), HbE/HbCS (n=2), and HbEE/HbCS (n=1) was also shown to have some degree of increased susceptibility to the oxidant stress. However the parasite in HbE erythrocytes, both homozygote (n=3) and heterozygote (n=5) had normal degree of susceptibility, while that in (...)thal trait (n=6) was surprisingly shown to have decreased susceptibility to a wide range of Go used. The mechanisms of reduced parasite Viability due to H(,2)O(,2) were different. For normal and G6PD deficient erythrocytes, the effect of H(,2)O(,2) was mainly on the erythrocytes and caused decreased parasite growth and invasion, while for the thalassemic erythrocytes, indirect evidence of direct parasite killing by H(,2)O(,2) was found in addition to the direct damage on the erythrocytes. Using ferritin labelling technique, sialic acid was demonstrated as electron dense particles on the red cell membrane. It was quantitated intwo different aspects : particles per area on tangential section, and on perpendicular section. On tangentially sectioned membrane, significant reduction of sialic acid density was found in genetically abnormal erythrocytes with double heterozygosity (...)thal(,1)/HbCS (P=value < 0.001). No such change was found in other variant erythrocytes : homozygous HbE, (...)thal/HbE and homozygous HbCS. Irreqular distribution of sialic acid was demonstrated on the membrane of homozygous HbCS erythrocytes (P-value < 0.001), and also the (...)thal(,1)/HbCS (p=value < 0.001). In the in vitro culture with P. falciparum, studied on perpendicular section, a higher degree of irregular sialic acid distribution was found in infected red cells from both normal (P-valur < 0.01) and genetically abnormal erythrocytes : HbH disease,(...)thal(,1)/(...)thal(,2) (P-value < 0.05). Significant reduction of sialic acid density was noted in infected erythrocytes from normal subject as compared to non-infected control (P-value < 0.001). The reduction in sialic acid density and/or irregular distribution may be a contributing factor leading to increased destruction of the red cells by the reticulo-endothelial system.