Normal erythrocytes have biconcave discoid shape that presents large surface area with higher cell surface to volume ratio than that of spherical shape. This appears to allow membrane internalization required for Plasmodium falciparum (Pf) invasion into erythrocytes. Indeed abnormal erythrocyte shape with decreased surface area to volume ratio such as hereditary spherocytosis limits invasion of the parasite. In the present study, using several agents to induce erythrocyte shape changes, we examined whether echinocytic shape change with membrane projections in opposite direction to membrane internalizations and/or stomatocytic shape change with decreased surface area to volume ratio that would be required for internalization, prevent Pf invasion. Having microscopically confirmed echinocytic and/or stomatocytic shape changes and also measured extensibility using an ektacytometer of the treated cells, subsequent Pf invasion assay was performed and parasitaemia determined. Both sodium flouride (NaF) and phospholipase A 2 (PLA 2) induced echinocytic change whereas phospholipase D (PLD), sphingomyelinase (SMase) and chlorpromazine (CPZ) caused stomatocytic change with decreased extensibility of erythrocytes. In both situations, Pf invasion was prevented, indicating that biconcave discoid shape of normal erythrocytes with high surface to volume ratio is required for membrane internalization when Pf invades into erythrocytes.