Although changes in the mechanical properties of infected red cells may contribute to the pathophysiology of malaria, such changes have not previously been described in detail. In this study, the physical properties of individual cells from both clinical and cultured samples infected with Plasmodium falciparum were tested using micropipette aspiration techniques. Cells containing ring forms took about 50% longer to enter 3 microns pipettes compared with nonparasitised cells, and there was a similar increase in the critical pressure required to induce cell entry. These abnormalities were similar in clinical and cultured samples. More mature cultured parasites (ie, trophozoites and schizonts containing pigment) caused much greater loss of deformability, with entry time and pressure increased four to sixfold. The decrease in deformability of the ring forms was attributable to a deficit in cell surface area/volume ratio (based on micropipette measurement of the surface area and volume of individual cells) and slight stiffening of the cell membrane (shear elastic modulus increased 13%, as measured by pipette aspiration of small membrane tongues). Measurement of the rate of cell shape recovery indicated that the membrane of parasitised cells was not more viscous. The main factor in the drastic loss of deformability of the trophozoites and schizonts was the presence of the large very resistant parasite itself. Otherwise, the cell surface area/volume deficit was slightly less and membrane rigidification slightly greater compared with ring forms. The above abnormalities should cause the trophozoites and schizonts to have great difficulty in traversing splenic or marrow sinuses and could contribute to microvascular occlusion and sequestration. On the other hand, the ring forms may be expected to circulate relatively unhindered.