This article successfully prepared the red blood cell-shaped microspheres via electrospraying. The polymer solution was comprised of polyether sulfone (PES) and dimethyl sulfoxide (DMSO), and the hydrophilic polyethylene glycol (PEG) was added to regulate and control the structure of the microspheres. When the solution concentration was 7.6 wt % and PES/PEG proportion was 10 : 5 while preparing microspheres, the shape and diameter of the microspheres was the most similar to that of erythrocyte. The results suggested that the forming mechanism of the red blood cell-shaped microspheres be related to two aspects. One is that the microspheres had relatively weak mechanical strength because of the sponge pores internal nanostructure. The other is that the existence of residual solvents and water within the microspheres would dissolve the gel phase PES and then further weaken mechanical strength of the outer layer of the microspheres, which caused the structural changes on the top layer of the spheres, that is, the top layer collapsed, and the microspheres finally turned into the red blood cell-shaped microspheres. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011.